Lactone integrin antagonists

ABSTRACT

The present invention relates to a class of compounds represented by the Formula I.  
                 
 
     or a pharmaceutically acceptable salt thereof, pharmaceutical compositions comprising compounds of the Formula I, and methods of selectively inhibiting or antagonizing the α v β 3  and/or the α v β 5  integrin.

[0001] The present application claims priority under Title 35, UnitedStates Code, §119 of U.S. Provisional applications Serial No. 60/235,617filed Sep. 27, 2000 and Ser. No. 60/241,633 filed Oct. 10, 2000.

FIELD OF THE INVENTION

[0002] The present invention relates to pharmaceutical agents which areα_(v)β₃ and/or α_(v)β₅ integrin antagonists and as such are useful inpharmaceutical compositions and in methods for treating conditionsmediated by α_(v)β₃ and/or α_(v)β₅ integrins.

BACKGROUND OF THE INVENTION

[0003] Integrins are a group of cell surface glycoproteins which mediatecell adhesion and therefore are useful mediators of cell adhesioninteractions which occur during various biological processes. Integrinsare heterodimers composed of noncovalently linked α and β polypeptidesubunits. Currently eleven different α subunits have been identified andsix different β subunits have been identified. The various α subunitscan combine with various β subunits to form distinct integrins.

[0004] The integrin identified as α_(v)β₃ (also known as the vitronectinreceptor) has been identified as an integrin which plays a role invarious conditions or disease states including tumor metastasis, solidtumor growth (neoplasia), osteoporosis (Ross, et al., J. Biol, Chem.,1987, 262, 7703), Paget's disease, humoral hypercalcemia of malignancy(Carron et al., Cancer Res. 1998, 58, 1930), osteopenia (Lark et al., JBone Miner Res. 2001, 16, 319), endometriosis (Healy et al., Hum.Reproductive Update, 1998, 4, 736), angiogenesis, including tumorangiogenesis (Cheresh, Cancer Metastasis Rev., 1991, 10, 3-10 andBrooks, et al., Cell, 1994, 79, 1157), retinopathy including maculardegeneration (Friedlander et al., Proc. Natl. Acad. Sci USA 1996, 93,9764), arthritis, including rheumatoid arthritis (Badger et al.,Arthritis Rheum, 2001, 44, 128), periodontal disease, psoriasis andsmooth muscle cell migration (e.g. restenosis and artherosclerosis,(Brown et al., Cardiovascular Res., 1994, 28, 1815). The compounds ofthe present invention are α_(v)β₃ antagonists and can be used, alone orin combination with other therapeutic agents, in the treatment ormodulation of various conditions or disease states described above.Additionally, it has been found that such agents would be useful asantivirals, antifungals and antimicrobials. Thus, compounds whichselectively antagonize α_(v)β₃ would be beneficial for treating suchconditions.

[0005] The integrin α_(v)β₅ plays a role in neovascularization.Antagonists of the α_(v)β₅ integrin will inhibit neovascularization andwill be useful for treating and preventing angiogenesis metastasis,tumor growth, macular degeneration and diabetic retionopathy. M. C.Friedlander, et al., Science, 270, 1500-1502 (1995) disclose that amonoclonal antibody for α_(v)β₅ inhibits VEFG-induced angogenesis in therabbit cornea and the chick chorioallantoic membrane model. Therefore,it would be useful to antagonize both the α_(v)β₅ and the α_(v)β₃receptor. Such “mixed α_(v)β₅/α_(v)β₃ antagonists” or “dualα_(v)β₃/α_(v)β₅ antagonists” would be useful for treating or preventingangiogenesis, tumor metastasis, tumor growth, diabetic retinopathy,macular degeneration, atherosclerosis and osteoporosis.

[0006] It has been shown that the α_(v)β₃ integrin and other α_(v)containing integrins bind to a number of Arg-Gly-Asp (RGD) containingmatrix macromolecules. Compounds containing the RGD sequence mimicextracellular matrix ligands so as to bind to cell surface receptors.However, it is also known that RGD peptides in general are non-selectivefor RGD dependent integrins. For example, most RGD peptides which bindto α_(v)β₃ also bind to α_(v)β₅, α_(v)β₁ and α_(IIb)β₃. Antagonism ofplatelet α_(IIb)β₃ (also known as the fibrinogen receptor) is known toblock platelet aggregation in humans. In order to avoid bleedingside-effects when treating the conditions or disease states associatedwith the integrin α_(v)β₃, it would be beneficial to develop compoundswhich are selective antagonists of α_(v)β₃ as opposed to α_(IIb)β₃.

[0007] Further, it has not been established in the art that sparingα_(v)β₆ integrin would be a beneficial property to be incorporated inthe design of antagonists of α_(v)β₃. Rather, α_(v)β₆ has beenidentified as a target for antagonists because it is higly expressed inmany carcinoma cell lines, and has been shown to enchance theproliferative capacity of a colon carcinoma cell line both in vivo andin vitro (Agrez et al., 1994, J. Cell Biol. 127, 547). Additionally,α_(v)β₆ is expressed during the later stages of wound healing andremains expressed until the wound is closed (See Christofidou-Solomidou,et al., 1997 American J. of Pathol., 151, 975), and therefore it isbelieved that α_(v)β₆ plays a role in the remodeling of the vasculatureduring the later stages of angiogenesis. Accordingly, antagonists ofα_(v)β₆ are seen as useful in treating or preventing cancer byinhibiting tumor growth and metastasis (see, for example, U.S. Pat. No.6,211,191).

[0008] Tumor cell invasion occurs by a three step process: 1) tumor cellattachment to extracellular matrix; 2) proteolytic dissolution of thematrix; and 3) movement of the cells through the dissolved barrier. Thisprocess can occur repeatedly and can result in metastases at sitesdistant from the original tumor.

[0009] Seftor et al. (Proc. Natl. Acad. Sci. USA, Vol. 89 (1992)1557-1561) have shown that the α_(v)β₃ integrin has a biologicalfunction in melanoma cell invasion. Montgomery et al., (Proc. Natl.Acad. Sci. USA, Vol. 91 (1994) 8856-60) have demonstrated that theintegrin α_(v)β₃ expressed on human melanoma cells promotes a survivalsignal, protecting the cells from apoptosis. Mediation of the tumor cellmetastatic pathway by interference with the α_(v)β₃ integrin celladhesion receptor to impede tumor metastasis would be beneficial.

[0010] Brooks et al. (Cell, Vol. 79 (1994) 1157-1164) have demonstratedthat antagonists of α_(v)β₃ provide a therapeutic approach for thetreatment of neoplasia (inhibition of solid tumor growth) since systemicadministration of α_(v)β₃ antagonists causes dramatic regression ofvarious histologically distinct human tumors.

[0011] The adhesion receptor integrin α_(v)β₃ was identified as a markerof angiogenic blood vessels in chick and man and therefore such receptorplays a critical role in angiogenesis or neovascularization.Angiogenesis is characterized by the invasion, migration andproliferation of smooth muscle and endothelial cells. Antagonists ofα_(v)β₃ inhibit this process by selectively promoting apoptosis of cellsin neovasculature. The growth of new blood vessels, or angiogenesis,also contributes to pathological conditions such as diabetic retinopathyincluding macular degeneration (Adamis et al., Amer. J. Ophthal., Vol.118, (1994) 445-450) and rheumatoid arthritis (Peacock et al., J. Exp.Med., Vol. 175, (1992), 1135-1138). Therefore, α_(v)β₃ antagonists wouldbe useful therapeutic agents for treating such conditions associatedwith neovascularization (Brooks et al., Science, Vol. 264, (1994),569-571).

[0012] It has been reported that the cell surface receptor α_(v)β₃ isthe major integrin on osteoclasts responsible for attachment to bone.Osteoclasts cause bone resorption and when such bone resorbing activityexceeds bone forming activity it results in osteoporosis (loss of bone),which leads to an increased number of bone fractures, incapacitation andincreased mortality. Antagonists of α_(v)β₃ have been shown to be potentinhibitors of osteoclastic activity both in vitro [Sato et al., J. Cell.Biol., Vol. 111 (1990) 1713-1723] and in vivo [Fisher et al.,Endocrinology, Vol. 132 (1993) 1411-1413]. Antagonism of α_(v)β₃ leadsto decreased bone resorption and therefore restores a normal balance ofbone forming and resorbing activity. Thus it would be beneficial toprovide antagonists of osteoclast α_(v)β₃ which are effective inhibitorsof bone resorption and therefore are useful in the treatment orprevention of osteoporosis.

[0013] The role of the α_(v)β₃ integrin in smooth muscle cell migrationalso makes it a therapeutic target for prevention or inhibition ofneointimal hyperplasia which is a leading cause of restenosis aftervascular procedures (Choi et al., J. Vasc. Surg. Vol. 19(1) (1994)125-34). Prevention or inhibition of neointimal hyperplasia bypharmaceutical agents to prevent or inhibit restenosis would bebeneficial.

[0014] White (Current Biology, Vol. 3(9)(1993) 596-599) has reportedthat adenovirus uses α_(v)β₃ for entering host cells. The integrinappears to be required for endocytosis of the virus particle and may berequired for penetration of the viral genome into the host cellcytoplasm. Thus compounds which inhibit α_(v)β₃ would find usefulness asantiviral agents.

SUMMARY OF THE INVENTION

[0015] The compounds of this invention are 1) α_(v)β₃ integrinantagonists; or 2) α_(v)β₅ integrin antagonists; or 3) mixed or dualα_(v)β₃/α_(v)β₅ antagonists. The present invention includes compoundswhich inhibit the respective integrins and also includes pharmaceuticalcompositions comprising such compounds. The present invention furtherprovides for methods for treating or preventing conditions mediated bythe α_(v)β₃ and/or α_(v)β₅ receptors in a mammal in need of suchtreatment comprising administering a therapeutically effective amount ofthe compounds of the present invention and pharmaceutical compositionsof the present invention. Administration of such compounds andcompositions of the present invention inhibits angiogenesis, tumormetastasis, tumor growth, osteoporosis, Paget's disease, humoralhypercalcemia of malignancy, retinopathy, macular degeneration,arthritis, periodontal disease, smooth muscle cell migration, includingrestenosis and artherosclerosis, and viral diseases.

[0016] The compounds of the present invention further show greaterselectivity for the α_(v)β₃ and/or α_(v)β₅ integrin than for the α_(v)β₆integrin. It has been found that the selective antagonism of the α_(v)β₃integrin is desirable in that the α_(v)β₆ integrin may play a role innormal physiological processes of tissue repair and cellular turnoverthat routinely occur in the skin and pulmonary tissue, and theinhibition of this function can be deleterious. Therefore, compounds ofthe present invention which selectively inihibit the α_(v)β₃ integrin asopposed to the α_(v)β₆ integrin have reduced side-effects associatedwith inhibtion of the α_(v)β₆ integrin.

[0017] The present invention relates to a class of compounds representedby the Formula I.

[0018] or a pharmaceutically acceptable salts thereof wherein

[0019] Y is selected from the group consisting of N—R¹, O, and S;

[0020] y and z are independently selected from an integer selected form0, 1, 2 and 3;

[0021] A is N or C;

[0022] R¹ is selected from the group consisting of H, alkyl, aryl,hydroxy, alkoxy, cyano, nitro, amino, alkenyl, alkynyl, amido,alkylcarbonyl, arylcarbonyl, alkoxycarbonyl, aryloxycarbonyl,haloalkylcarbonyl, haloalkoxycarbonyl, alkylthiocarbonyl,arylthiocarbonyl, acyloxymethoxycarbonyl, alkyl optionally substitutedwith one or more substituent selected from lower alkyl, halogen,hydroxyl, haloalkyl, cyano, nitro, carboxyl, amino, alkoxy, aryl or aryloptionally substituted with one or more halogen, haloalkyl, lower alkyl,alkoxy, cyano, alkylsulfonyl, alkylthio, nitro, carboxyl, amino,hydroxyl, sulfonic acid, sulfonamide, aryl, fused aryl, monocyclicheterocycles, or fused monocyclic heterocycles, aryl optionallysubstituted with one or more substituent selected from halogen,haloalkyl, hydroxy, lower alkyl, alkoxy, methylenedioxy, ethylenedioxy,cyano, nitro, alkylthio, alkylsulfonyl, sulfonic acid, sulfonamide,carboxyl derivatives, amino, aryl, fused aryl, monocyclic heterocyclesand fused monocyclic heterocycle, monocyclic heterocycles, andmonocyclic heterocycles optionally substituted with one or moresubstituent selected from halogen, haloalkyl, lower alkyl, alkoxy,amino, nitro, hydroxy, carboxyl derivatives, cyano, alkylthio,alkylsulfonyl, sulfonic acid, sulfonamide, aryl or fused aryl; or

[0023] R¹ taken together with R⁸ forms a 4-12 membered dinitrogencontaining heterocycle optionally substituted with one or moresubstituent selected from the group consisting of lower alkyl, hydroxy,keto, alkoxy, halo, phenyl, amino, carboxyl or carboxyl ester, and fusedphenyl; or

[0024] R¹ taken together with R⁸ forms a 5 membered heteroaromatic ringoptionally substituted with one or more substituent selected from loweralkyl, phenyl and hydroxy; or

[0025] R¹ taken together with R⁸ forms a 5 membered heteroaromatic ringfused with a phenyl group;

[0026] R⁸ (when not taken together with R¹) and R⁹ are independentlyselected from the group consisting of H, alkyl, alkenyl, alkynyl,aralkyl, amino, alkylamino, hydroxy, alkoxy, arylamino, amido,alkylcarbonyl, arylcarbonyl, alkoxycarbonyl, aryloxy, aryloxycarbonyl,haloalkylcarbonyl, haloalkoxycarbonyl, alkylthiocarbonyl,arylthiocarbonyl, acyloxymethoxycarbonyl, cycloalkyl, bicycloalkyl,aryl, acyl, benzoyl, alkyl optionally substituted with one or moresubstituent selected from lower alkyl, halogen, hydroxy, haloalkyl,cyano, nitro, carboxyl derivatives, amino, alkoxy, thio, alkylthio,sulfonyl, aryl, aralkyl, aryl optionally substituted with one or moresubstituent selected from halogen, haloalkyl, lower alkyl, alkoxy,methylenedioxy, ethylenedioxy, alkylthio, haloalkylthio, thio, hydroxy,cyano, nitro, carboxyl derivatives, aryloxy, amido, acylamino, amino,alkylamino, dialkylamino, trifluoroalkoxy, trifluoromethyl, sulfonyl,alkylsulfonyl, haloalkylsulfonyl, sulfonic acid, sulfonamide, aryl,fused aryl, monocyclic heterocycles, fused monocyclic heterocycles, aryloptionally substituted with one or more substituent selected fromhalogen, haloalkyl, lower alkyl, alkoxy, methylenedioxy, ethylenedioxy,alkylthio, haloalkylthio, thio, hydroxy, cyano, nitro, carboxylderivatives, aryloxy, amido, acylamino, amino, alkylamino, dialkylamino,trifluoroalkoxy, trifluoromethylsulfonyl, alkylsulfonyl, sulfonic acid,sulfonamide, aryl, fused aryl, monocyclic heterocycles, or fusedmonocyclic heterocycles, monocyclic heterocycles, monocyclicheterocycles optionally substituted with one or more substituentselected from halogen, haloalkyl, lower alkyl, alkoxy, aryloxy, amino,nitro, hydroxy, carboxyl derivatives, cyano, alkylthio, alkylsulfonyl,aryl, fused aryl, monocyclic and bicyclic heterocyclicalkyls, —SO₂R¹⁰wherein R¹⁰ is selected from the group consisting of alkyl, aryl andmonocyclic heterocycles, all optionally substituted with one or moresubstituent selected from the group consisting of halogen, haloalkyl,alkyl, alkoxy, cyano, nitro, amino, acylamino, trifluoroalkyl, amido,alkylaminosulfonyl, alkylsulfonyl, alkylsulfonylamino, alkylamino,dialkylamino, trifluoromethylthio, trifluoroalkoxy,trifluoromethylsulfonyl, aryl, aryloxy, thio, alkylthio, and monocyclicheterocycles; and

[0027] wherein R¹⁰ is defined as above; or

[0028] NR⁸ and R⁹ taken together form a 4-12 membered mononitrogencontaining monocyclic or bicyclic ring optionally substituted with oneor more substituent selected from lower alkyl, carboxyl derivatives,aryl or hydroxy and wherein said ring optionally contains a heteroatomselected from the group consisting of O, N and S; or

[0029] wherein Y′ is selected from the group consisting of alkyl,cycloalkyl, bicycloalkyl, aryl, monocyclic heterocycles, alkyloptionally substituted with aryl which can also be optionallysubstituted with one or more substituent selected from halo, haloalkyl,alkyl, nitro, hydroxy, alkoxy, aryloxy, aryl, or fused aryl, aryloptionally substituted with one or more substituent selected from halo,haloalkyl, hydroxy, alkoxy, aryloxy, aryl, fused aryl, nitro,methylenedioxy, ethylenedioxy, or alkyl, alkynyl, alkenyl, —S—R¹¹ and—OR¹¹ wherein R¹¹ is selected from the group consisting of H, alkyl,aralkyl, aryl, alkenyl, and alkynyl, or R¹¹ taken together with R⁸ formsa 4-12 membered mononitrogen and monosulfur or monooxygen containingheterocyclic ring optionally substituted with lower alkyl, hydroxy,keto, phenyl, carboxyl or carboxyl ester, and fused phenyl, or R¹¹ takentogether with R⁸ is thiazole, oxazole, benzoxazole, or benzothiazole;

[0030] R⁸ is defined as above; or

[0031] Y¹ (when Y¹ is carbon) taken together with R⁸ forms a 4-12membered mononitrogen or dinitrogen containing ring optionallysubstituted with alkyl, aryl, keto or hydroxy; or

[0032] wherein R¹ and R⁸ taken together form a 5-8 membered dinitrogencontaining heterocycle optionally substituted with one or moresubstituent selected from the group consisting of lower alkyl, hydroxy,keto, phenyl, or carboxyl derivatives; and R⁹ is selected from the groupconsisting of alkylcarbonyl, arylcarbonyl, alkoxycarbonyl,aryloxycarbonyl, haloalkylcarbonyl, haloalkoxycarbonyl,alkylthiocarbonyl, arylthiocarbonyl, or acyloxymethoxycarbonyl; or

[0033] wherein R¹ and R⁸ taken together form a 5-8 membered dinitrogencontaining heterocycle optionally substituted with hydroxy, keto,phenyl, or alkyl; and R⁹ are both selected from the group consisting ofalkylcarbonyl, arylcarbonyl, alkoxycarbonyl, aryloxycarbonyl,haloalkylcarbonyl, haloalkoxycarbonyl, alkylthiocarbonyl,arylthiocarbonyl and acyloxymethoxycarbonyl;

[0034] R², R³ and R⁴ are independently selected from one or moresubstituent selected from thegroup consisting of H, alkyl, hydroxy,alkoxy, aryloxy, halogen, haloalkyl, haloalkoxy, nitro, amino,alkylamino, acylamino, dialkylamino, cyano, alkylthio, alkylsulfonyl,carboxyl derivatives, trihaloacetamide, acetamide, aryl, fused aryl,cycloalkyl, thio, monocyclic heterocycles, fused monocyclicheterocycles, and X, wherein X is defined as above;

[0035] R⁵, R⁶ and R⁷ are independently selected from the groupconsisting of hydrogen, alkyl, alkenyl, alkynyl, aryl, carboxylderivatives, haloalkyl, cycloalkyl, monocyclic heterocycles, monocyclicheterocycles optionally substituted with alkyl, halogen, haloalkyl,cyano, hydroxy, aryl, fused aryl, nitro, alkoxy, aryloxy, alkylsulfonyl,arylsulfonyl, sulfonamide, thio, alkylthio, carboxyl derivatives, amino,amido, alkyl optionally substituted with one or more of halo, haloalkyl,hydroxy, alkoxy, aryloxy, thio, alkylthio, alkynyl, alkenyl, alkyl,arylthio, alkylsulfoxide, alkylsulfonyl, arylsulfoxide, arylsulfonyl,cyano, nitro, amino, alkylamino, dialkylamino, alkylsulfonamide,arylsulfonamide, acylamide, carboxyl derivatives, sulfonamide, sulfonicacid, phosphonic acid derivatives, phosphinic acid derivatives, aryl,arylthio, arylsulfoxide, or arylsulfone all optionally substituted onthe aryl ring with halo, alkyl, haloalkyl, cyano, nitro, hydroxy,carboxyl derivatives, alkoxy, aryloxy, amino, alkylamino, dialkylamino,amido, aryl, fused aryl, monocyclic heterocycles, and fused monocyclicheterocycles, monocyclic heterocyclicthio, monocyclicheterocyclicsulfoxide, and monocyclic heterocyclic sulfone, which can beoptionally substituted with halo, haloalkyl, nitro, hydroxy, alkoxy,fused aryl, or alkyl, alkylcarbonyl, haloalkylcarbonyl, andarylcarbonyl, aryl optionally substituted in one or more positions withhalo, haloalkyl, alkyl, alkoxy, aryloxy, methylenedioxy, ethylenedioxy,alkylthio, haloalkylthio, thio, hydroxy, cyano, nitro, acyloxy, carboxylderivatives, carboxyalkoxy, amido, acylamino, amino, alkylamino,dialkylamino, trifluoroalkoxy, trifluoromethylsulfonyl, alkylsulfonyl,sulfonic acid, sulfonamide, aryl, fused aryl, monocyclic heterocyclesand fused monocyclic heterocycles.

[0036] The compounds according to Formula I can exist in variousisomers, enantiomers, tautomers, racemates and polymorphs, and all suchforms are meant to be included.

[0037] It is another object of the invention to provide pharmaceuticalcompositions comprising compounds of the Formula I. Such compounds andcompositions are useful in selectively inhibiting or antagonizing theα_(v)β₃ and/or α_(v)β₅ integrins and therefore in another embodiment thepresent invention relates to a method of selectively inhibiting orantagonizing the α_(v)β₃ and/or α_(v)β₅ integrin. The invention furtherinvolves treating or inhibiting pathological conditions associatedtherewith such as osteoporosis, humoral hypercalcemia of malignancy,Paget's disease, tumor metastasis, solid tumor growth (neoplasia),angiogenesis, including tumor angiogenesis, retinopathy includingmacular degeneration and diabetic retinopathy, arthritis, includingrheumatoid arthritis, periodontal disease, psoriasis, smooth muscle cellmigration and restenosis in a mammal in need of such treatment.Additionally, such pharmaceutical agents are useful as antiviral agents,and antimicrobials.

DETAILED DESCRIPTION

[0038] In its broadest sense, the invention relates to compoundsrepresented by Formula I

[0039] The present invention relates to compound represented by FormulaI

[0040] or a pharmaceutically acceptable salts thereof wherein

[0041] Y is selected from the group consisting of N—R¹, O, and S;

[0042] y and z are independently selected from an integer selected form0, 1, 2 and 3;

[0043] A is N or C;

[0044] R¹ is selected from the group consisting of H, alkyl, aryl,hydroxy, alkoxy, cyano, nitro, amino, alkenyl, alkynyl, amido,alkylcarbonyl, arylcarbonyl, alkoxycarbonyl, aryloxycarbonyl,haloalkylcarbonyl, haloalkoxycarbonyl, alkylthiocarbonyl,arylthiocarbonyl, acyloxymethoxycarbonyl, alkyl optionally substitutedwith one or more substituent selected from lower alkyl, halogen,hydroxyl, haloalkyl, cyano, nitro, carboxyl, amino, alkoxy, aryl or aryloptionally substituted with one or more halogen, haloalkyl, lower alkyl,alkoxy, cyano, alkylsulfonyl, alkylthio, nitro, carboxyl, amino,hydroxyl, sulfonic acid, sulfonamide, aryl, fused aryl, monocyclicheterocycles, or fused monocyclic heterocycles, aryl optionallysubstituted with one or more substituent selected from halogen,haloalkyl, hydroxy, lower alkyl, alkoxy, methylenedioxy, ethylenedioxy,cyano, nitro, alkylthio, alkylsulfonyl, sulfonic acid, sulfonamide,carboxyl derivatives, amino, aryl, fused aryl, monocyclic heterocyclesand fused monocyclic heterocycle, monocyclic heterocycles, andmonocyclic heterocycles optionally substituted with one or moresubstituent selected from halogen, haloalkyl, lower alkyl, alkoxy,amino, nitro, hydroxy, carboxyl derivatives, cyano, alkylthio,alkylsulfonyl, sulfonic acid, sulfonamide, aryl or fused aryl; or

[0045] R¹ taken together with R⁸ forms a 4-12 membered dinitrogencontaining heterocycle optionally substituted with one or moresubstituent selected from the group consisting of lower alkyl, hydroxy,keto, alkoxy, halo, phenyl, amino, carboxyl or carboxyl ester, and fusedphenyl; or

[0046] R¹ taken together with R⁸ forms a 5 membered heteroaromatic ringoptionally substituted with one or more substituent selected from loweralkyl, phenyl and hydroxy; or

[0047] R¹ taken together with R⁸ forms a 5 membered heteroaromatic ringfused with a phenyl group;

[0048] R⁸ (when not taken together with R¹) and R⁹ are independentlyselected from the group consisting of H, alkyl, alkenyl, alkynyl,aralkyl, amino, alkylamino, hydroxy, alkoxy, arylamino, amido,alkylcarbonyl, arylcarbonyl, alkoxycarbonyl, aryloxy, aryloxycarbonyl,haloalkylcarbonyl, haloalkoxycarbonyl, alkylthiocarbonyl,arylthiocarbonyl, acyloxymethoxycarbonyl, cycloalkyl, bicycloalkyl,aryl, acyl, benzoyl, alkyl optionally substituted with one or moresubstituent selected from lower alkyl, halogen, hydroxy, haloalkyl,cyano, nitro, carboxyl derivatives, amino, alkoxy, thio, alkylthio,sulfonyl, aryl, aralkyl, aryl optionally substituted with one or moresubstituent selected from halogen, haloalkyl, lower alkyl, alkoxy,methylenedioxy, ethylenedioxy, alkylthio, haloalkylthio, thio, hydroxy,cyano, nitro, carboxyl derivatives, aryloxy, amido, acylamino, amino,alkylamino, dialkylamino, trifluoroalkoxy, trifluoromethyl, sulfonyl,alkylsulfonyl, haloalkylsulfonyl, sulfonic acid, sulfonamide, aryl,fused aryl, monocyclic heterocycles, fused monocyclic heterocycles, aryloptionally substituted with one or more substituent selected fromhalogen, haloalkyl, lower alkyl, alkoxy, methylenedioxy, ethylenedioxy,alkylthio, haloalkylthio, thio, hydroxy, cyano, nitro, carboxylderivatives, aryloxy, amido, acylamino, amino, alkylamino, dialkylamino,trifluoroalkoxy. trifluoromethylsulfonyl, alkylsulfonyl, sulfonic acid,sulfonamide, aryl, fused aryl, monocyclic heterocycles, or fusedmonocyclic heterocycles, monocyclic heterocycles, monocyclicheterocycles optionally substituted with one or more substituentselected from halogen, haloalkyl, lower alkyl, alkoxy, aryloxy, amino,nitro, hydroxy, carboxyl derivatives, cyano, alkylthio, alkylsulfonyl,aryl, fused aryl, monocyclic and bicyclic heterocyclicalkyls, —SO₂R¹⁰wherein R¹⁰ is selected from the group consisting of alkyl, aryl andmonocyclic heterocycles, all optionally substituted with one or moresubstituent selected from the group consisting of halogen, haloalkyl,alkyl, alkoxy, cyano, nitro, amino, acylamino, trifluoroalkyl, amido,alkylaminosulfonyl, alkylsulfonyl, alkylsulfonylamino, alkylamino,dialkylamino, trifluoromethylthio, trifluoroalkoxy,trifluoromethylsulfonyl, aryl, aryloxy, thio, alkylthio, and monocyclicheterocycles; and

[0049] wherein R¹⁰ is defined as above; or

[0050] NR⁸ and R⁹ taken together form a 4-12 membered mononitrogencontaining monocyclic or bicyclic ring optionally substituted with oneor more substituent selected from lower alkyl, carboxyl derivatives,aryl or hydroxy and wherein said ring optionally contains a heteroatomselected from the group consisting of O, N and S; or

[0051] wherein Y′ is selected from the group consisting of alkyl,cycloalkyl, bicycloalkyl, aryl, monocyclic heterocycles, alkyloptionally substituted with aryl which can also be optionallysubstituted with one or more substituent selected from halo, haloalkyl,alkyl, nitro, hydroxy, alkoxy, aryloxy, aryl, or fused aryl, aryloptionally substituted with one or more substituent selected from halo,haloalkyl, hydroxy, alkoxy, aryloxy, aryl, fused aryl, nitro,methylenedioxy, ethylenedioxy, or alkyl, alkynyl, alkenyl, —S—R¹¹ and—OR¹¹ wherein R¹¹ is selected from the group consisting of H, alkyl,aralkyl, aryl, alkenyl, and alkynyl, or R¹¹ taken together with R⁸ formsa 4-12 membered mononitrogen and monosulfur or monooxygen containingheterocyclic ring optionally substituted with lower alkyl, hydroxy,keto, phenyl, carboxyl or carboxyl ester, and fused phenyl, or R¹¹ takentogether with R⁸ is thiazole, oxazole, benzoxazole, or benzothiazole;

[0052] R⁸ is defined as above; or

[0053] Y¹ (when Y¹ is carbon) taken together with R⁸ forms a 4-12membered mononitrogen or dinitrogen containing ring optionallysubstituted with alkyl, aryl, keto or hydroxy; or

[0054] wherein R¹ and R⁸ taken together form a 5-8 membered dinitrogencontaining heterocycle optionally substituted with one or moresubstituent selected from the group consisting of lower alkyl, hydroxy,keto, phenyl, or carboxyl derivatives; and R⁹ is selected from the groupconsisting of alkylcarbonyl, arylcarbonyl, alkoxycarbonyl,aryloxycarbonyl, haloalkylcarbonyl, haloalkoxycarbonyl,alkylthiocarbonyl, arylthiocarbonyl, or acyloxymethoxycarbonyl; or

[0055] wherein R¹ and R⁸ taken together form a 5-8 membered dinitrogencontaining heterocycle optionally substituted with hydroxy, keto,phenyl, or alkyl; and R⁹ are both selected from the group consisting ofalkylcarbonyl, arylcarbonyl, alkoxycarbonyl, aryloxycarbonyl,haloalkylcarbonyl, haloalkoxycarbonyl, alkylthiocarbonyl,arylthiocarbonyl and acyloxymethoxycarbonyl;

[0056] R², R³ and R⁴ are independently selected from one or moresubstituent selected from thegroup consisting of H, alkyl, hydroxy,alkoxy, aryloxy, halogen, haloalkyl, haloalkoxy, nitro, amino,alkylamino, acylamino, dialkylamino, cyano, alkylthio, alkylsulfonyl,carboxyl derivatives, trihaloacetamide, acetamide, aryl, fused aryl,cycloalkyl, thio, monocyclic heterocycles, fused monocyclicheterocycles, and X, wherein X is defined as above;

[0057] R⁵, R⁶ and R⁷ are independently selected from the groupconsisting of hydrogen, alkyl, alkenyl, alkynyl, aryl, carboxylderivatives, haloalkyl, cycloalkyl, monocyclic heterocycles, monocyclicheterocycles optionally substituted with alkyl, halogen, haloalkyl,cyano, hydroxy, aryl, fused aryl, nitro, alkoxy, aryloxy, alkylsulfonyl,arylsulfonyl, sulfonamide, thio, alkylthio, carboxyl derivatives, amino,amido, alkyl optionally substituted with one or more of halo, haloalkyl,hydroxy, alkoxy, aryloxy, thio, alkylthio, alkynyl, alkenyl, alkyl,arylthio, alkylsulfoxide, alkylsulfonyl, arylsulfoxide, arylsulfonyl,cyano, nitro, amino, alkylamino, dialkylamino, alkylsulfonamide,arylsulfonamide, acylamide, carboxyl derivatives, sulfonamide, sulfonicacid, phosphonic acid derivatives, phosphinic acid derivatives, aryl,arylthio, arylsulfoxide, or arylsulfone all optionally substituted onthe aryl ring with halo, alkyl, haloalkyl, cyano, nitro, hydroxy,carboxyl derivatives, alkoxy, aryloxy, amino, alkylamino, dialkylamino,amido, aryl, fused aryl, monocyclic heterocycles, and fused monocyclicheterocycles, monocyclic heterocyclicthio, monocyclicheterocyclicsulfoxide, and monocyclic heterocyclic sulfone, which can beoptionally substituted with halo, haloalkyl, nitro, hydroxy, alkoxy,fused aryl, or alkyl, alkylcarbonyl, haloalkylcarbonyl, andarylcarbonyl, aryl optionally substituted in one or more positions withhalo, haloalkyl, alkyl, alkoxy, aryloxy, methylenedioxy, ethylenedioxy,alkylthio, haloalkylthio, thio, hydroxy, cyano, nitro, acyloxy, carboxylderivatives, carboxyalkoxy, amido, acylamino, amino, alkylamino,dialkylamino, trifluoroalkoxy, trifluoromethylsulfonyl, alkylsulfonyl,sulfonic acid, sulfonamide, aryl, fused aryl, monocyclic heterocyclesand fused monocyclic heterocycles.

[0058] In another embodiment, the invention is represented by Formula II

[0059] or a pharmaceutically acceptable salt thereof, wherein R₁ and R₂are selected from a group consisting of hydrogen, hydroxy alkylhaloalkyl and halogen.

[0060] The invention further relates to pharmaceutical compositionscontaining therapeutically effective amounts of the compounds of FormulaI or II.

[0061] The invention also relates to a method of selectively inhibitingor antagonizing the α_(v)β₃ integrin and/or the α_(v)β₅ integrin andmore specifically relates to a method of inhibiting bone resorption,periodontal disease, osteoporosis, humoral hypercalcemia of malignancy,Paget's disease, tumor metastasis, solid tumor growth (neoplasia),angiogenesis, including tumor angiogenesis, retinopathy includingmacular degeneration and diabetic retinopathy, arthritis, includingrheumatoid arthritis, smooth muscle cell migration and restenosis byadministering a therapeutically effective amount of a compound of theFormula I to achieve such inhibition together with a pharmaceuticallyacceptable carrier. More specifically it has been found that itadvantageous to administer compounds which are α_(v)β₃ and/or α_(v)β₅antagonists which compounds selectively inhibit the α_(v)β₃ and/orα_(v)β₅ integrin as opposed to the α_(v)β₆ integrin. It has now beenfound that such selectivity is beneficial in reducing unwantedside-effects.

[0062] To evaluate the selectivity of compounds between the integrinsα_(v)β₃ and α_(v)β₆, cell-based assays are established using the 293human embryonic kidney cell line as described herein. The compoundsdisclosed herein have shown significant selectivity between theintegrins α_(v)β₃ and α_(v)β₆. The selective antagonism of the α_(v)β₃integrin is viewed as desirable in this class of compounds, as α_(v)β₆may also play a role in normal physiological processes of tissue repairand cellular turnover that routinely occur in the skin and pulmonarytissues.

[0063] As used herein, the terms “alkyl” or “lower alkyl” refer to astraight chain or branched chain hydrocarbon radicals having from about1 to about 10 carbon atoms, and more preferably 1 to about 6 carbonatoms. Examples of such alkyl radicals are methyl, ethyl, n-propyl,isopropyl, n-butyl, isobutyl, sec-butyl, t-butyl, pentyl, neopentyl,hexyl, isohexyl, and the like.

[0064] As used herein the terms “alkenyl” or “lower alkenyl” refer tounsaturated acyclic hydrocarbon radicals containing at least one doublebond and 2 to about 6 carbon atoms, which carbon-carbon double bond mayhave either cis or trans geometry within the alkenyl moiety, relative togroups substituted on the double bond carbons. Examples of such groupsare ethenyl, propenyl, butenyl, isobutenyl, pentenyl, hexenyl and thelike.

[0065] As used herein the terms “alkynyl” or “lower alkynyl” refer toacyclic hydrocarbon radicals containing one or more triple bonds and 2to about 6 carbon atoms. Examples of such groups are ethynyl, propynyl,butynyl, pentynyl, hexynyl and the like.

[0066] The term “cycloalkyl” as used herein means saturated or partiallyunsaturated cyclic carbon radicals containing 3 to about 8 carbon atomsand more preferably 4 to about 6 carbon atoms. Examples of suchcycloalkyl radicals include cyclopropyl, cyclopropenyl, cyclobutyl,cyclopentyl, cyclohexyl, 2-cyclohexen-1-yl, and the like.

[0067] The term “aryl” as used herein denotes aromatic ring systemscomposed of one or more aromatic rings. Preferred aryl groups are thoseconsisting of one, two or three aromatic rings. The term embracesaromatic radicals such as phenyl, pyridyl, naphthyl, thiophene, furan,biphenyl and the like.

[0068] As used herein, the term “cyano” is represented by a radical

[0069] The terms “hydroxy” and “hydroxyl” as used herein are synonymousand are represented by a radical

[0070] The term “lower alkylene” or “alkylene” as used herein refers todivalent linear or branched saturated hydrocarbon radicals of 1 to about6 carbon atoms.

[0071] As used herein the term “alkoxy” refers to straight or branchedchain oxy containing radicals. Examples of alkoxy groups encompassedinclude methoxy, ethoxy, n-propoxy, n-butoxy, isopropoxy, isobutoxy,sec-butoxy, t-butoxy and the like.

[0072] As used herein the terms “arylalkyl” or “aralkyl” refer to aradical of the formula

[0073] wherein R²¹ is aryl as defined above and R²² is an alkylene asdefined above. Examples of aralkyl groups include benzyl, pyridylmethyl,naphthylpropyl, phenethyl and the like.

[0074] As used herein the term “nitro” is represented by a radical

[0075] As used herein the term “halo” or “halogen” refers to bromo,chloro, fluoro or iodo.

[0076] As used herein the term “haloalkyl” refers to alkyl groups asdefined above substituted with one or more of the same or different halogroups at one or more carbon atom. Examples of haloalkyl groups includetrifluoromethyl, dichloroethyl, fluoropropyl and the like.

[0077] As used herein the term “carboxyl” or “carboxy” refers to aradical of the formula —COOH.

[0078] As used herein the term “carboxyl ester” refers to a radical ofthe formula —COOR²³ wherein R²³ is selected from the group consisting ofH, alkyl, aralkyl or aryl as defined above.

[0079] As used herein the term “carboxyl derivative” refers to a radicalof the formula

[0080] wherein Y⁶ and Y⁷ are independently selected from the groupconsisting of O, N or S and R²³ is selected from the group consisting ofH, alkyl, aralkyl and aryl as defined above.

[0081] As used herein the term “amino” is represented by a radical ofthe formula —NH₂.

[0082] As used herein the term “alkylsulfonyl” or “alkylsulfone” refersto a radical of the

[0083] wherein R²⁴ is alkyl as defined above.

[0084] As used herein the term “alkylthio” refers to a radical of theformula —SR²⁴ wherein R²⁴ is alkyl as defined above.

[0085] As used herein the term “sulfonic acid” refers to a radical ofthe

[0086] wherein R²⁵ is alkyl as defined above.

[0087] As used herein the term “sulfonamide” or “sulfonamido” refers toa radical

[0088] wherein R⁷ and R⁸ are as defined above.

[0089] As used herein the term “fused aryl” refers to an aromatic ringsuch as the aryl groups defined above fused to one or more phenyl rings.Embraced by the term “fused aryl” is the radical naphthyl and the like.

[0090] As used herein the terms “monocyclic heterocycle” or “monocyclicheterocyclic” refer to a monocyclic ring containing from 4 to about 12atoms, and more preferably from 5 to about 10 atoms, wherein 1 to 3 ofthe atoms are heteroatoms selected from the group consisting of oxygen,nitrogen and sulfur with the understanding that if two or more differentheteroatoms are present at least one of the heteroatoms must benitrogen. Representative of such monocyclic heterocycles are imidazole,furan, pyridine, oxazole, pyran, triazole, thiophene, pyrazole,thiazole, thiadiazole, and the like.

[0091] As used herein the term “fused monocyclic heterocycle” refers toa monocyclic heterocycle as defined above with a benzene fused thereto.Examples of such fused monocyclic heterocycles include benzofuran,benzopyran, benzodioxole, benzothiazole, benzothiophene, benzimidazoleand the like.

[0092] As used herein the term “methylenedioxy” refers to the radical

[0093] and the term “ethylenedioxy” refers to the radical

[0094] As used herein the term “4-12 membered dinitrogen containingheterocycle refers to a radical of the formula

[0095] wherein m is 1 or 2 and R¹⁹ is H, alkyl, aryl, or aralkyl andmore preferably refers to 4-9 membered ring and includes rings such asimidazoline.

[0096] As used herein the term “5-membered optionally substitutedheteroaromatic ring” includes for example a radical of the formula

[0097] and “5-membered heteroaromatic ring fused with a phenyl” refersto such a “5-membered heteroaromatic ring” with a phenyl fused thereto.Representative of such 5-membered heteroaromatic rings fused with aphenyl is benzimidazole.

[0098] As used herein the term “bicycloalkyl” refers to a bicyclichydrocarbon radical containing 6 to about 12 carbon atoms which issaturated or partially unsaturated.

[0099] As used herein the term “acyl” refers to a radical of the formula

[0100] wherein R²⁶ is alkyl, alkenyl, alkynyl, aryl or aralkyl andoptionally substituted thereon as defined above. Encompassed by suchradical are the groups acetyl, benzoyl and the like.

[0101] As used herein the term “thio” refers to a radical of the formula

[0102] As used herein the term “sulfonyl” refers to a radical of theformula

[0103] wherein R²⁷ is alkyl, aryl or aralkyl as defined above.

[0104] As used herein the term “haloalkylthio” refers to a radical ofthe formula —S—R²⁸ wherein R²⁸ is haloalkyl as defined above.

[0105] As used herein the term “aryloxy” refers to a radical of theformula

[0106] wherein R²⁹ is aryl as defined above.

[0107] As used herein the term “acylamino” refers to a radical of theformula

[0108] wherein R³⁰ is alkyl, aralkyl or aryl as defined above.

[0109] As used herein the term “amido” refers to a radical of theformula

[0110] As used herein the term “alkylamino” refers to a radical of theformula —NHR³² wherein R³² is alkyl as defined above.

[0111] As used herein the term “dialkylamino” refers to a radical of theformula —NR³³R³⁴ wherein R³³ and R³⁴ are the same or different alkylgroups as defined above.

[0112] As used herein the term “trifluoromethyl” refers to a radical ofthe formula

[0113] As used herein the term “trifluoroalkoxy” refers to a radical ofthe formula

[0114] wherein R³⁵ is a bond or an alkylene as defined above.

[0115] As used herein the term “alkylaminosulfonyl” or “aminosulfonyl”refers to a radical of the formula

[0116] wherein R³⁶ is alkyl as defined above.

[0117] As used herein the term “alkylsulfonylamino” or“”alkylsulfonamide” refers to a radical of the formula

[0118] wherein R³⁶ is alkyl as defined above.

[0119] As used herein the term “trifluoromethylthio” refers to a radicalof the formula

[0120] As used herein the term “trifluoromethylsulfonyl” refers to aradical of the formula

[0121] As used herein the term “4-12 membered mono-nitrogen containingmonocyclic or bicyclic ring” refers to a saturated or partiallyunsaturated monocyclic or bicyclic ring of 4-12 atoms and morepreferably a ring of 4-9 atoms wherein one atom is nitrogen. Such ringsmay optionally contain additional heteroatoms selected from nitrogen,oxygen or sulfur. Included within this group are morpholine, piperidine,piperazine, thiomorpholine, pyrrolidine, proline, azacycloheptene andthe like.

[0122] As used herein the term “benzyl” refers to the radical

[0123] As used herein the term “phenethyl” refers to the radical

[0124] As used herein the term “4-12 membered mono-nitrogen containingmonosulfur or monooxygen containing heterocyclic ring” refers to a ringconsisting of 4 to 12 atoms and more preferably 4 to 9 atoms wherein atleast one atom is a nitrogen and at least one atom is oxygen or sulfur.Encompassed within this definition are rings such as thiazoline and thelike.

[0125] As used herein the term “arylsulfonyl” or “arylsulfone” refers toa radical of the formula

[0126] wherein R³⁷ is aryl as defined above.

[0127] As used herein the terms “alkylsulfoxide” or “arylsulfoxide”refer to radicals of the formula

[0128] wherein R³⁸ is, respectively, alkyl or aryl as defined above.

[0129] As used herein the term “arylthio” refers to a radical of theformula

[0130] wherein R⁴² is aryl as defined above.

[0131] As used herein the term “monocyclic heterocycle thio” refers to aradical of the formula

[0132] wherein R⁴³ is a monocyclic heterocycle radical as defined above.

[0133] As used herein the terms “monocyclic heterocycle sulfoxide” and“monocyclic heterocycle sulfone” refer, respectively, to radicals

[0134] wherein R⁴³ is a monocyclic heterocycle radical as defined above.

[0135] As used herein the term “alkylcarbonyl” refers to a radical ofthe formula

[0136] wherein R⁵⁰ is alkyl as defined above.

[0137] As used herein the term “arylcarbonyl” refers to a radical of theformula

[0138] wherein R⁵¹ is aryl as defined above.

[0139] As used herein the term “alkoxycarbonyl” refers to a radical ofthe formula

[0140] wherein R⁵² is alkoxy as defined above.

[0141] As used herein the term “aryloxycarbonyl” refers to a radical ofthe formula

[0142] wherein R⁵¹ is aryl as defined above.

[0143] As used herein the term “haloalkylcarbonyl” refers to a radicalof the formula

[0144] R⁵³ is haloalkyl as defined above.

[0145] As used herein the term “haloalkoxycarbonyl” refers to a radicalof the formula

[0146] 4wherein R⁵³ is haloalkyl as defined above.

[0147] As used herein the term “alkylthiocarbonyl” refers to a radicalof the formula

[0148] wherein R⁵⁰ is alkyl as defined above.

[0149] As used herein the term “arylthiocarbonyl” refers to a radical ofthe formula

[0150] wherein R⁵¹ is aryl as defined above.

[0151] As used herein the term “acyloxymethoxycarbonyl” refers to aradical of the formula

[0152] wherein R⁵⁴ is acyl as defined above.

[0153] As used herein the term “arylamino” refers to a radical of theformula R⁵¹—NH— wherein R⁵¹ is aryl as defined above.

[0154] As used herein the term “acyloxy” refers to a radical of theformula R⁵⁵—O— wherein R⁵⁵ is acyl as defined above.

[0155] As used herein the term “alkenylalkyl” refers to a radical of theformula R⁵⁰—R⁵⁷— wherein R⁵⁰ is an alkenyl as defined above and R⁵⁷ isalkylene as defined above.

[0156] As used herein the term “alkenylene” refers to a linearhydrocarbon radical of 1 to about 8 carbon atoms containing at least onedouble bond.

[0157] As used herein the term “alkoxyalkyl” refers to a radical of theformula R⁵⁶—R⁵⁷— wherein R⁵⁶ is alkoxy as defined above and R⁵⁷ isalkylene as defined above.

[0158] As used herein the term “alkynylalkyl” refers to a radical of theformula R⁵⁹—R⁶⁰— wherein R⁵⁹ is alkynyl as defined as above and R⁶⁰ isalkylene as defined as above.

[0159] As used herein the term “alkynylene” refers to divalent alkynylradicals of 1 to about 6 carbon atoms.

[0160] As used herein the term “allyl” refers of a radical of theformula —CH₂CH═CH₂.

[0161] As used herein the term “aminoalkyl” refers to a radical of theformula H₂N—R⁶¹ wherein R⁶¹ is alkylene as defined above.

[0162] As used herein the term “benzoyl” refers to the aryl radicalC₆H₅—CO—.

[0163] As used herein the term “carboxamide” or “carboxamido” refer to aradical of the formula —CO—NH₂.

[0164] As used herein the term “carboxyalkyl” refers to a radicalHOOC—R⁶²— wherein R⁶² is alkylene as defined as above.

[0165] As used herein the term “carboxylic acid” refers to the radical—COOH.

[0166] As used herein the term “ether” refers to a radical of theformula R⁶³—O— wherein R⁶³ is selected from the group consisting ofalkyl, aryl and heteroaryl.

[0167] As used herein the term “haloalkylsulfonyl” refers to a radicalof the formula

[0168] wherein the R⁶⁴ is haloalkyl as defined above.

[0169] As used herein the term “heteroaryl” refers to an aryl radicalcontain at least one heteroatom.

[0170] As used herein the term “hydroxyalkyl” refers to a radical of theformula HO—R⁶⁵— wherein R⁶⁵ is alkylene as defined above.

[0171] As used herein the term “keto” refers to a carbonyl group joinedto 2 carbon atoms.

[0172] As used herein the term “lactone” refers to an anhydro cyclicester produced by intramolecular condensation of a hydroxy acid with theelimination of water.

[0173] As used herein the term “olefin” refers to an unsaturatedhydrocarbon radical of the type C_(n)H_(2n).

[0174] As used herein the term “sulfone” refers to a radical of theformula R⁶⁶—SO₂—.

[0175] As used herein the term “thioalkyl” refers to a radical of theformula R⁷⁷—S— wherein R⁷⁷ is alkyl as defined above.

[0176] As used herein the term “thioether” refers to a radical of theformula R⁷⁸—S— wherein R⁷⁸ is alkyl aryl or heteroaryl.

[0177] As used herein the term “trifluoroalkyl” refers to an alkylradical as defined above substituted with three halo radicals as definedabove.

[0178] The term “composition” as used herein means a product whichresults from the mixing or combining of more than one element oringredient.

[0179] The term “pharmaceutically acceptable carrier”, as used hereinmeans a pharmaceutically acceptable material, composition or vehicle,such as a liquid or solid filler, diluent, excipient, solvent orencapsulating material, involved in carrying or transporting a chemicalagent.

[0180] The term “therapeutically effective amount” shall mean thatamount of drug or pharmaceutical agent that will elicit the biologicalor medical response of a tissue, system or animal that is being soughtby a researcher or clinician.

[0181] The following is a list of abbreviations and the correspondingmeanings as used interchangeably herein:

[0182]¹H-NMR=proton nuclear magnetic resonance

[0183] AcOH=acetic acid

[0184] BOC=tert-butoxycarbonyl

[0185] BuLi=butyl lithium

[0186] Cat.=catalytic amount

[0187] CH₂Cl₂=dichloromethane

[0188] CH₃CN=acetonitrile

[0189] CH₃I=iodomethane

[0190] CHN analysis=carbon/hydrogen/nitrogen elemental analysis

[0191] CHNCl analysis=carbon/hydrogen/nitrogen/chlorine elementalanalysis

[0192] CHNS analysis=carbon/hydrogen/nitrogen/sulfur elemental analysis

[0193] DEAD=diethylazodicarboxylate

[0194] DIAD=diisopropylazodicarboxylate

[0195] DI water=deionized water

[0196] DMA=N,N-dimethylacetamide

[0197] DMAC=N,N-dimethylacetamide

[0198] DMF=N,N-dimethylformamide

[0199] EDC=1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride

[0200] Et=ethyl

[0201] Et₂O=diethyl ether

[0202] Et₃N=triethylamine

[0203] EtOAc=ethyl acetate

[0204] EtOH=ethanol

[0205] FAB MS=fast atom bombardment mass spectroscopy

[0206] g=gram(s)

[0207] HOBT=1-hydroxybenzotriazole hydrate

[0208] HPLC=high performance liquid chromatography

[0209] i-Pr=iso propyl

[0210] i-Prop=iso propyl

[0211] K₂CO₃=potassium carbonate

[0212] KMnO₄=potassium permanganate

[0213] KOH=potassium hydroxide

[0214] KSCN=potassium thiocyanate

[0215] L=Liter

[0216] LiOH=lithium hydroxide

[0217] Me=methyl

[0218] MeOH=methanol

[0219] mg=milligram

[0220] MgSO₄=magnesium sulfate

[0221] ml=milliliter

[0222] mL=milliliter

[0223] MS=mass spectroscopy

[0224] NaH—sodium hydride

[0225] NaHCO₃=sodium bicarbonate

[0226] NaOH=sodium hydroxide

[0227] NaOMe=sodium methoxide

[0228] NH₄ ⁺HCO₂ ⁻=ammonium formate

[0229] NMR=nuclear magnetic resonance

[0230] Pd=palladium

[0231] Pd/C=palladium on carbon

[0232] Ph=phenyl

[0233] Pt=platinum

[0234] Pt/C=platinum on carbon

[0235] RPHPLC=reverse phase high performance liquid chromatography

[0236] RT=room temperature

[0237] t-BOC=tert-butoxycarbonyl

[0238] TFA=trifluoroacetic acid

[0239] THF=tetrahydrofuran

[0240] TLC—thin layer chromatography

[0241] TMS=trimethylsilyl

[0242] Δ=heating the reaction mixture

[0243] The compounds as shown above can exist in various isomeric formsand all such isomeric forms are meant to be included. Tautomeric formsare also included as well as pharmaceutically acceptable salts of suchisomers and tautomers.

[0244] In the structures and formulas herein, a bond drawn across a bondof a ring can be to any available atom on the ring.

[0245] The term “pharmaceutically acceptable salt” refers to a saltprepared by contacting a compound of Formula I or II with an acid whoseanion is generally considered suitable for human consumption. For use inmedicine, the salts of the compounds of this invention are non-toxic“pharmaceutically acceptable salts.” Salts encompassed within the term“pharmaceutically acceptable salts” refer to non-toxic salts of thecompounds of this invention which are generally prepared by reacting thefree base with a suitable organic or inorganic acid. Representativesalts include the following: acetate, benzenesulfonate, benzoate,bicarbonate, bisulfate, bitartrate, borate, bromide, calcium, camsylate,carbonate, chloride, clavulanate, citrate, dihydrochloride, edetate,edisylate, estolate, esylate, fumarate, gluceptate, gluconate,glutamate, glycollylarsanilate, hexylresorcinate, hydrabamine,hydrobromide, hydrochloride, hydroxynaphthoate, iodide, isothionate,lactate, lactobionate, laurate, malate, maleate, mandelate, mesylate,methylbromide, methylnitrate, methylsulfate, mucate, napsylate, nitrate,N-methylgucamine ammonium salt, oleate, oxalate, pamoate (embonate),palmitate, pantothenate, phosphate/disphosphate, polygalacturonate,salicylate, stearate, sulfate, subacetate, succinate, tannate, tartrate,teoclate, tosylate, triethiodide and valerate. Furthermore, where thecompounds of the invention carry an acidic moiety, suitablepharmaceutically acceptable salts thereof may include alkali metalsalts, e.g., sodium or potassium salts, alkaline earth metal salts,e.g., calcium or magnesium salts; and salts formed with suitable organicligands, e.g., quaternary ammonium salts. All of the pharmacologicallyacceptable salts may be prepared by conventional means. (See Berge etal., J Pharm. Sci., 66(1), 1-19 (1977) for additional examples ofpharmaceutically acceptable salts.)

[0246] The compounds of the present invention can have chiral centersand occur as racemates, racemic mixtures, diastereomeric mixtures, andas individual diastereomers or enantiomers, with all isomeric formsincluded in the present invention. Therefore, where a compound ischiral, the separate enantiomers or diastereomers, substantially free ofthe other, are included within the scope of the present invention;further included are all mixtures of the enantiomers or diastereomers.Also included within the scope of the invention are polymorphs, orhydrates or other modifiers of the compounds of invention.

[0247] The present invention includes within its scope prodrugs of thecompounds of this invention. In general, such prodrugs will befunctional derivatives of the compounds of this invention which arereadily convertible in vivo into the required compound. For example,prodrugs of a carboxylic acid may include an ester, an amide, anortho-ester, or heterocycles such as tetrazole. Thus, in the methods oftreatment of the present invention, the term “administering” shallencompass the treatment of the various conditions described with thecompound specifically disclosed or with a compound which may not bespecifically disclosed, but which converts to the specified compound invivo after administration to the patient. Conventional procedures forthe selection and preparation of suitable prodrug derivatives aredescribed, for example, in “Design of Prodrugs,” ed. H. Bundgaard,Elsevier, 1985, which is incorporated by reference herein in itsentirety. Metabolites of these compounds include active species producedupon introduction of compounds of this invention into the biologicalmilieu.

[0248] For the selective inhibition or antagonism of α_(v)β₃ and/orα_(v)β₅ integrins, compounds of the present invention may beadministered orally, parenterally, or by inhalation spray, or topicallyin unit dosage formulations containing conventional pharmaceuticallyacceptable carriers, adjuvants and vehicles. The term parenteral as usedherein includes, for example, subcutaneous, intravenous, intramuscular,intrasternal, transmuscular infusion techniques or intraperitonally.

[0249] The compounds of the present invention are administered by anysuitable route in the form of a pharmaceutical composition adapted tosuch a route, and in a dose effective for the treatment intended.Therapeutically effective doses of the compounds required to prevent orarrest the progress of or to treat the medical condition are readilyascertained by one of ordinary skill in the art using preclinical andclinical approaches familiar to the medicinal arts.

[0250] Accordingly, the present invention provides a method of treatingconditions mediated by selectively inhibiting or antagonizing theα_(v)β₃ and/or α_(v)β₅ cell surface receptor which method comprisesadministering a therapeutically effective amount of a compound selectedfrom the class of compounds depicted in the above formulas, wherein oneor more compound is administered in association with one or morenon-toxic, pharmaceutically acceptable carriers and/or diluents and/oradjuvants (collectively referred to herein as “carrier” materials) andif desired other active ingredients. The present invention also providesa method for selective inhibition of the α_(v)β₃ and/or α_(v)β₅ cellsurface receptors with a reduced α_(v)β₆ inhibition. Another aspect ofthe invention provides a method for inhibiting bone resorption, treatingosteoporosis, inhibiting humoral hypercalcemia of malignancy, treatingPaget's disease, inhibiting tumor metastasis, inhibiting neoplasia(solid tumor growth), inhibiting angiogenesis including tumorangiogenesis, treating retinopathy including macular degeneration anddiabetic retinopathy, inhibiting arthritis, psoriasis and periodontaldisease, and inhibiting smooth muscle cell migration includingrestenosis.

[0251] In another embodiment, the present invention provides a methodfor selective antagonism of the α_(v)β₃ and/or α_(v)β₅ cell surfacereceptors over α_(IIb)β₃, and in a further embodiment, also over theα_(v)β₆ integrin receptor. Evidence of the toxicity of β₆ integrinantagonism indicates that it may be beneficial to spare antagonism of β₆when designing α_(v)β₃ antagonists, in addition to sparing α_(IIb)β₃.Selectivite inhibition refers to a selectivity ratio of at least 10,more preferably 50, and even more preferably of at least 100.Selectivity ratio refers to the selectivity of the IC₅₀ of α_(v)β₆ orα_(IIb)β₃ over the selectivity of the IC₅₀ of β₃.

[0252] Based upon standard laboratory experimental techniques andprocedures well known and appreciated by those skilled in the art, aswell as comparisons with compounds of known usefulness, the compounds ofFormula I or II can be used in the treatment of patients suffering fromthe above pathological conditions. One skilled in the art will recognizethat selection of the most appropriate compound of the invention iswithin the ability of one with ordinary skill in the art and will dependon a variety of factors including assessment of results obtained instandard assay and animal models.

[0253] Treatment of a patient afflicted with one of the pathologicalconditions comprises administering to such a patient an amount ofcompound of the Formula I which is therapeutically effective incontrolling the condition or in prolonging the survivability of thepatient beyond that expected in the absence of such treatment. As usedherein, the term “inhibition” of the condition refers to slowing,interrupting, arresting or stopping the condition and does notnecessarily indicate a total elimination of the condition. It isbelieved that prolonging the survivability of a patient, beyond being asignificant advantageous effect in and of itself, also indicates thatthe condition is beneficially controlled to some extent.

[0254] As stated previously, the compounds of the invention can be usedin a variety of biological, prophylactic or therapeutic areas. It iscontemplated that these compounds are useful in prevention or treatmentof any disease state or condition wherein the α_(v)β₃ and/or α_(v)β₅integrin plays a role.

[0255] The dosage regimen for the compounds and/or compositionscontaining the compounds is based on a variety of factors, including thetype, age, weight, sex and medical condition of the patient; theseverity of the condition; the route of administration; and the activityof the particular compound employed. Thus the dosage regimen may varywidely. Dosage levels of the order from about 0.01 mg to about 100 mgper kilogram of body weight per day are useful in the treatment of theabove-indicated conditions.

[0256] Oral dosages of the present invention, when used for theindicated effects, will range between about 0.01 mg per kg of bodyweight per day (mg/kg/day) to about 100 mg/kg/day, preferably 0.01 to 10mg/kg/day, and most preferably 0.1 to 1.0 mg/kg/day. For oraladministration, the compositions are preferably provided in the form oftablets containing 0.01, 0.05, 0.1, 0.5, 1.0, 2.5, 5.0, 10.0, 15.0,25.0, 50.0, 100, 200 and 500 milligrams of the active ingredient for thesymptomatic adjustment of the dosage to the patient to be treated. Amedicament typically contains from about 0.01 mg to about 500 mg of theactive ingredient, preferably, from about 1 mg to about 100 mg of activeingredient. Intravenous doses will range from about 0.1 to about 10mg/kg/minute during a constant rate infusion. Compounds of the presentinvention may be administered in a single daily dose, or the total dailydosage may be administered in divided doses of two, three or four timesdaily. Furthermore, compounds of the present invention can beadministered in intranasal form via topical use of suitable intranasalvehicles, or via transdermal routes, using those forms of transdermalskin patches well known to those of ordinary skill in the art. To beadministered in the form of a transdermal delivery system, the dosageadministration may be continuous rather than intermittant throughout thedosage regiment.

[0257] For administration to a mammal in need of such treatment, thecompounds in a therapeutically effective amount are ordinarily combinedwith one or more adjuvants appropriate to the indicated route ofadministration. The compounds may be admixed with lactose, sucrose,starch powder, cellulose esters of alkanoic acids, cellulose alkylesters, talc, stearic acid, magnesium stearate, magnesium oxide, sodiumand calcium salts of phosphoric and sulphuric acids, gelatin, acacia,sodium alginate, polyvinylpyrrolidone, and/or polyvinyl alcohol, andtableted or encapsulated for convenient administration. Alternatively,the compounds may be dissolved in water, polyethylene glycol, propyleneglycol, ethanol, corn oil, cottonseed oil, peanut oil, sesame oil,benzyl alcohol, sodium chloride, and/or various buffers. Other adjuvantsand modes of administration are well and widely known in thepharmaceutical art.

[0258] The pharmaceutical compositions useful in the present inventionmay be subjected to conventional pharmaceutical operations such assterilization and/or may contain conventional pharmaceutical adjuvantssuch as preservatives, stabilizers, wetting agents, emulsifiers,buffers, etc.

[0259] The following Schemes are intended to be merely illustrative ofthe present invention, and not limiting thereof in either scope orspirit. Those skilled in the art will readily understand that knownvariations of the conditions and processes described in the Schemes canbe used to make the embodiments of the invention.

[0260] The following Examples are intended to be illustrative and notintended to limit the scope of the invention.

EXAMPLE 1

[0261]

[0262] Synthesis of 3-amino-5-oxo-3S-furan hydrochloride

[0263] A solution of the Boc-aspartimol-γ-benzylester (0.5 g,Tetrahedron Lett .32, (7), 923, 1991) in dry benzene (10.0 mL)containing p-toluenesulfonic acid (0.32 g) was heated to reflux for 1.5h. under anhydrous conditions. The reaction mixture was cooled, dilutedwith ether and filtered the precipitate. It was washed with ether, anddried to give 0.38 g of the desired lactone as its p-toluenesufonatesalt: ¹H-NMR (DMSO-d₆) δ8.14 (br, 2H), 7.46 (d, 2H, J=8.0 Hz), 7.09 (d,2H, J=8.0 Hz), 4.46 (m, 1H), 4.24 (m, 1H), 4.19(m, 1H), 2.96 (dd, 1H),2.47 (dd, 2H), 2.2 (, 3H); MS: m/z 102 (MH⁺)

[0264] Ex 1b

[0265] Alternate preparation of of 3-amino-5-oxo-3S-furan hydrochloride.

[0266] N-tBoc-L-aspartic acid, β-benzyl ester (10.0 mmole) was dissolvedin 10 mL of tetrahydrofuran (THF) and added drop-wise over a period of30 min to a 0° C. solution of BH₃—THF (20 mL, 20.0 mmole) under argon.After the mixture was stirred for an additional 1-2 hr at 0° C., thereaction was quenched by drop-wise addition of 10% acetic acid inmethanol and the solvent evaporated. The oil residue was dissolved inethyl acetate and extracted with 1N HCl, water, and 1M NH₄HCO₃. Theethyl acetate layer was dried (Na₂SO₄) and volatiles evaporated to givean oil that could be crystalized from isopropanol/hexane (mp 56-57° C.):¹H NMR (CDCL₃) δ1.45 (s, 9H), 2.65 (d, 2H), 3.68 (d, 2H), 5.12 (s, 2H),5.25 (m, 1H), 7.35 (m, 5H).

[0267] The resulting 3-N-tBoc-amino-4-hydroxy-butyric acid benzyl ester(20 g. 64 mmole) was stirred in 200 mL dichloromethane at roomtemperature for 16 hr in the presence of a catalytic amount of camphorsulfonic acid. Solvent was removed in vacuo and the crude productpurified by flash chromatography (Merck 60 silica gel, ethylacetate/hexane/1% triethylamine). The N-tBoc-3-aminolactone was isolatedas a white solid (5.4 g).

[0268] The 3-N-tBoc-aminolactone (5.0 g, 25 mmole) isolate was dissolvedin 20 mL 4N HCl/dioxane. After 45 minutes at 25° C., 10 mL of 4NHCl/dioxane was added and after 1 hr the excess HCl was removed invacuo. The resulting solution deposited white crystals upon standing.These were filtered and dried to give 2.9 g of the desired product asthe hydrochloride salt. ¹H NMR (d₆ DMSO) δ2.55 (dd, J₁=18.3 Hz, J₂=2.5Hz), 3.0 (dd, 1H, J₁=8.5 Hz, J₂=18.3 Hz), 4.1 (m, 1H), 4.35 (dd, 1H,J₁=10.5 Hz, J₂=2.7 Hz), 4.5 (dd, 1H, J₁=10.5 Hz, J₂=6.5 Hz); MS (FAB)102.1 (M+H).

[0269] Ex 1c

[0270] 3-amino-5-oxo-3S-furan hydrochloride (2.9 g, 21 mmol) wasdissolved in DMF (123 mL) and cooled to 0° C. under a nitrogenatmosphere. N-Boc-Gly-OSu (5.4 g, 20 mmol) was added, followed by4methylmorpholine (2.3 mL, 21 mmol). After the solution was stirred 18hours, it was diluted with brine and extracted twice with EtOAc. Thecombined organic layers were washed with H₂O, dried (Na₂SO₄), filtered,and concentrated in vacuo. The residue was purified by chromatography onsilica gel (eluent: EtOAc) to give a colorless oil (4.7 g, 87%). ¹H NMR(CDCl₃) δ1.46 (s, 9H), 2.51 (dd, 1H), 2.89 (dd, 1H), 3.82 (s, 2H), 4.25(dd, 1H), 4.54 (dd, 1H), 4.72 (m, 1H).

[0271] Ex 1d

[0272] The colorless oil from Ex 1c (3.2 g, 12.4 mmol) was dissolved in4N HCl dioxane (30 mL). After stirring 2.5 hours at ambient temperature,the excess HCl was removed in vacuo. The white solid material wasfiltered and dried (2.4 g, 98%). ¹H NMR (CD₃OD) δ2.51 (dd, 1H), 2.92(dd, 1H), 3.68 (s, 2H), 4.28 (dd, 1H), 4.57 (dd, 1H), 4.63 (m, 1H).EI-MS m/z 159 (MH⁺).

[0273] Ex 1e

[0274] The amine hydrochloride from Ex 1d (950 mg, 4.9 mmol) and Acid A(1.4 g, 4.9 mmol, prepared according to U.S. Pat. No. 6,013,651, ExampleH) were combined and slurried in DMF/CH₂Cl₂ (12 mL, 1:1) at ambienttemperature under a nitrogen atmosphere. 1,3-Diisopropylcarbodiimide(0.9 mL, 5.9 mmoL) was added, followed by 4-methylmorpholine (0.5 mL,4.9 mmol). After stirring 18 hours, the solution was filtered through apad of Celite and the filtrate concentrated in vacuo. The resulting oilwas purified by reverse-phase HPLC (H₂O/CH₃CN) to afford the titlecompound as a white solid (671 mg, 20%). ¹H NMR (DMSO-d₆) δ2.37 (dd,1H), 2.90 (dd, 1H), 3.16 (dd, 2H), 3.35 (dd, 2H), 3.82 (d, 2H), 4.09 (m,2H), 4.48 (m, 2H), 6.75 (t, 1H) 7.11 (t, 1H), 7.14 (m, 1H), 8.18 (s,2H), 8.54 (d, 1H), 8.63 (t, 1H), 9.71 (s, 1H). EI-MS m/z 392 (MH⁺).Anal. Calcd for C₁₇H₂₁N₅O₆+2.5 TFA+0.5 H₂O: C, 38.55; H, 3.60. Found: C,38.55; H, 3.87.

EXAMPLE 2

[0275]

[0276] Ex 2a

[0277] The amine hydrochloride from Ex 1d (950 mg, 4.9 mmol) and Acid B(1.3 g, 4.9 mmol, prepared using similar procedure according to U.S.Pat. No. 6,013,651, Example H) were combined and slurried in DMF/CH₂Cl₂(12 mL, 1:1) at ambient temperature under a nitrogen atmosphere.1,3-Diisopropylcarbodiimide (0.9 mL, 5.9 mmoL) was added, followed by4-methylmorpholine (0.5 mL, 4.9 mmol). After stirring 18 hours, thesolution was filtered through a pad of Celite and the filtrateconcentrated in vacuo. The resulting oil was purified by reverse-phaseHPLC (H₂O/CH₃CN) to afford the title compound as a light yellow solid(760 mg, 25%). ¹H NMR (DMSO-d₆) δ1.89 (m, 2H), 2.37 (dd, 1H), 2.89 (dd,1H), 3.16 (dd, 2H), 3.28 (m, 4H), 3.84 (d, 2H), 4.09 (m, 1H), 4.48 (m,2H), 6.75 (t, 1H) 7.11 (t, 1H), 7.14 (m, 1H), 8.32 (s, 2H), 8.54 (d,1H), 8.63 (t, 1H), 9.89 (s, 1H). EI-MS m/z 376 (MH⁺). Anal. Calcd forC₁₇H₂₁N₅O₅+2 TFA+0.3 H₂O: C, 41.43; H, 3.91; N, 11.50. Found: C, 41.21;H, 4.07; N, 11.74.

EXAMPLE 3

[0278]

[0279] Ex 3a

[0280] The amine hydrochloride from Ex 1d (950 mg, 4.9 mmol) and Acid C(1.0 g, 3.7 mmol, prepared using similar procedure according to U.S.Pat. No. 6,013,651, Example H) were combined and slurried in DMF/CH₂Cl₂(12 mL, 1:1) at ambient temperature under a nitrogen atmosphere.1,3-Diisopropylcarbodiimide (0.9 mL, 5.9 mmoL) was added, followed by4-methylmorpholine (0.5 mL, 4.9 mmol). After stirring 18 hours, thesolution was filtered through a pad of Celite and the filtrateconcentrated in vacuo. The resulting oil was purified by reverse-phaseHPLC (H₂O/CH₃CN) to afford the title compound as a light yellow solid(150 mg, 7%). ¹H NMR (DMSO-d₆) δ2.39 (dd, 1H), 2.90 (dd, 1H), 3.17 (dd,2H), 3.38 (dd, 2H), 3.87 (d, 2H), 4.10 (m, 2H), 4.48 (m, 2H), 7.36 (m,1H), 7.52 (t, 1H), 7.70 (m, 1H), 7.75 (m, 1H), 8.38 (s, 2H), 8.62 (d,1H), 8.83 (t, 1H), 10.08 (s, 1H). EI-MS m/z 376 (MH⁺). Anal. Calcd forC₁₇H₂₁N₅O₅+2 TFA+0.5 H₂O: C, 41.18; H, 3.95; N, 11.44. Found: C, 40.86;H, 3.90; N, 11.83.

EXAMPLE 4

[0281]

[0282] Ex 4a

[0283] The amine hydrochloride from Ex 1d (950 mg, 4.9 mmol) and Acid D(899 g, 3.5 mmol, prepared according to U.S. Pat. No. 6,028,223, Example236, Step B) were combined and slurried in DMF/CH₂Cl₂ (12 mL, 1:1) atambient temperature under a nitrogen atmosphere.1,3-Diisopropylcarbodiimide (0.9 mL, 5.9 mmoL) was added, followed by4-methylmorpholine (0.5 mL, 4.9 mmol). After stirring 18 hours, thesolution was filtered through a pad of Celite and the filtrateconcentrated in vacuo. The resulting oil was purified by reverse-phaseHPLC (H₂O/CH₃CN) to afford the title compound as a light yellow solid(600 mg, 30%). ¹H NMR (DMSO-d₆) δ1.89 (m, 2H), 2.39 (dd, 1H), 2.89 (dd,1H), 3.28 (m, 4H), 3.84 (d, 2H), 4.09 (m, 1H), 4.48 (m, 2H), 7.37 (m,1H), 7.53 (t, 1H), 7.70 (m, 1H), 7.74 (m, 1H), 8.29 (s, 2H), 8.61 (d,1H), 8.83 (t, 1H), 9.93 (s, 1H). EI-MS m/z 360 (MH⁺). Anal. Calcd forC₁₇H₂₁N₅O₄+1 TFA+1 H₂O+1 DMF: C, 46.81; H, 5.54; N, 14.89. Found: C,46.69; H, 5.21; N, 14.69.

EXAMPLE 5

[0284]

[0285] Ex 5a

[0286] The amine hydrochloride from Ex 1c (950 mg, 4.9 mmol) and Acid B(1.0 g, 3.5 mmol, prepared using similar procedure according to U.S.Pat. No. 6,028,223, Example38) were combined and slurried in DMF/CH₂Cl₂(12 mL, 1:1) at ambient temperature under a nitrogen atmosphere.1,3-Diisopropylcarbodiimide (0.9 mL, 5.9 mmoL) was added, followed by4-methylmorpholine (0.5 mL, 4.9 mmol). After stirring 18 hours, thesolution was filtered through a pad of Celite and the filtrateconcentrated in vacuo. The resulting oil was purified by reverse-phaseHPLC (H₂O/CH₃CN) to afford the title compound as a light yellow solid(600 mg, 30%). ¹H NMR (DMSO-d₆) δ1.89 (m, 2H), 2.39 (dd, 1H), 2.89 (dd,1H), 3.28 (m, 4H), 3.84 (d, 2H), 4.09 (m, 1H), 4.48 (m, 2H), 7.37(m,1H), 7.53 (t, 1H), 7.70 (m, 1H), 7.74 (m, 1H), 8.29 (s, 2H), 8.61 (d,1H), 8.83 (t, 1H), 9.93 (s, 1H). EI-MS m/z 360 (MH⁺). Anal. Calcd forC₁₇H₂₁N₅O₄+1 TFA+1 H₂O+1 DMF: C, 46.81; H, 5.54; N, 14.89. Found: C,46.69; H, 5.21; N, 14.69.

EXAMPLE 6

[0287]

[0288] Ex 6a

[0289]3-[(5-fluoro-1,4,5,6-tetrahydro-2-pyrimidinyl)amino]-5-hydroxybenzoicacid

[0290] Step A

[0291] To a solution of 1,3 diamino-2-fluoropropane (8.3 g), in DMF (100mL), was added triethylamine (10.0 mL), followed by the addition ofS-methylisothiourea (16 g) and the resulting mixture was stirred at roomtemperature. After 30 mins of stirring, the reaction mixture was heatedto 90° C., under anhydrous conditions for 3 h, when a light brownprecipitate was obtained. DMF was distilled in vacuo, residue wastriturated with water, and filtered. The precipitate was washedthoroughly with water, followed by acetonitrile, and dried in adesiccator in vacuo to afford 8.0 g of 8-6 as a light brown powder. Thiswas used as such in Step B.

[0292] Step B

[0293] To a chilled suspension of the above product (0.265 g, 0.0010mol) in anhydrous THF (5 mL) was added HCl/dioxane (4N, 0.52 mL, 2 eqiv)and stirred cold 1 h. The solvent was removed under reduced pressure toafford the desired hydrochloride salt 8-7 after drying (0.339 g, 99%):¹H-NMR (CD₃OD) δ7.38 (m, 1H), 7.33 (m, 1H), 5.15 (m, 1H), 3.63-3.4 (m,4H); HR-MS m/z (MH+) calcd C11H13N3OF3 (MH+) 254.0941, found 254.0944.

[0294] Ex 6b

[0295] To a solution of Acid F (0.57 g, 0.002 mol) in DMF (5.0 mL) wasadded isobutylchloroformate (0.25 mL), followed by the drop-wiseaddition of N-methyl-morpholine (0.26 mL) and the mixture was stirred at−10° C. under an atmosphere of argon (Scheme III). After 20 min, asolution of the amine generated by the addition of N-methyl-morpholine(0.26 mL) to a solution of glycine-t-butylester hydrochloride (0.4 g,0.0024 mol) in DMF (5.0 mL) was added and the resulting mixture wasstirred at room temperature for 6 h. DMF was distilled in vacuo, and theresidue was purified by reverse-phase HPLC using 10-90%acetonitrile/water at flow rate of 70 mL/min. The appropriate fractionswere combined and freeze dried to obtain 0.32 g of the desired^(t)butylester as a white powder. ¹H-NMR (CD₃OD) δ7.19 (m, 1H), 7.15 (d,1H, J=1.6 Hz), 6.82 (m, 1H), 5.20 (2t, 1H, J_(H.F)=44 Hz, J=2.4 Hz),3.98 (s, 2H), 3.65-3.45 (m, 4H), and 1.47 (s, 9H), HR-MS: m/z calcd forC₁₇H₂₄N₄O₄F (MH⁺) 367.1782, found 367.1776.

[0296] Ex 6c

[0297] A solution of the t-butylester (0.6 g, 0.00164 mol) as preparedin Ex 6b was stirred with trifluoroacetic acid (3.0 mL)at roomtemperature for 1 h and concentrated to dryness under reduced pressure.The resulting product (TFA salt) was suspended in toluene (5.0 mL) andconcentrated to dryness in vacuo, and dried in a desiccator for 4 h overNaOH pallets. This material was used as such in Ex 6d.

[0298] Ex 6d

[0299] The TFA salt from Ex 6c, was dissolved in dry DMF (5.0 mL), addedisobutylchloroformate (0.2 mL), followed by the addition ofN-methylmorpholine (0.2 mL) and stirred at −15 ° C. under argonatmosphere. After 30 min, the 3-amino-5-oxo-3S-furan (0.44 g, 0.0016mol) prepared in Ex 1a, and N-methylmorpholine (0.2 mL) were added andthe resulting mixture was stirred at −10° C. for an additional 30 min,and at room temperature for 2 h. The solvents were distilled in vacuoand the crude material was purified by reverse-phase HPLC using agradient of 10-90% acetonitrile/water at flow rate of 70 mL/min. Theappropriate fractions as revealed by mass spectrum of the fractions (MH⁺m/z 394) were combined and freeze dried to obtain the desired lactone asits p-toluenesulfonate salt (0.31 g): ¹H-NMR (CD₃OD) δ8.04 (br, 1H),7.68 (d, 2H, J=8.4 Hz), 7.22 (m, 2H), 7.17 (t 1H, J=2.0 Hz), 6.82 (m,1H), 5.19 (d, 1H, J=46.4 Hz), 4.58 (m 1H), 4.52 (m 1H), 4.21 (dd, 1H,J=2.8 Hz), 3.98 (s, 2H), 3.65-3.35 (m 4H), 2.90 (dd, 1H, J=8.4 Hz), 2.47(dd, 1H, J=3.6 Hz), 2.35 (s, 3H); HR-MS m/z calcd for C₁₇H₂₁N₅O₅F (MH⁺)394.1527, found 394.1527.

EXAMPLE 7

[0300]

[0301] The title compound is prepared according to procedure used in thepreparation of EXAMPLE 6 using the corresponding starting materials.

EXAMPLE 8

[0302]

[0303] To the mixture of 1 (900 mg, 3.0 mmol, prepared using similarprocedure described in EXAMPLE 6, step 6a, 6b, 6c) and pentafluorophenol(1.10 g, 6.0 mmol) in DMF (10 ml) was addedO-Benzotriazole-N,N,N′,N′-tetramethyl-uronium-hexafluoro-phosphate(HBTU) (1.14 g, 3.0 mmol) The mixture was stirred for two hours at roomtemperature. To this resulting mixture was added a solution of 2 (416mg, 3.0 mmol) and N-methyl morpholine (303 mg, 3.0 mmol) in DMF (5.0ml). After the mixture was stirred for 16 hours at room temperature, itwas quenched with water and the solvents were allowed to evaporatedunder reduced pressure. The residue was purified through preparativeHPLC (C-18 column, eluted with water/acetonitrile) to isolate desiredproduct 3 (750 mg) as a white amorphous solid. ¹HNMR(400 MHz, DMSO-d6,vs TMS) δ2.57(1H, dd, J=3.49, 3.57 Hz), 2.97(1H, dd, J=8.21, 8.20 Hz),3.82(4H, s), 4.06(2H, s), 4.27(1H, dd, J=3.06, 3.27 Hz), 4.56(1H, dd,J=9.50, 9.54 Hz), 4.62(1H, m), 7.48(1H, m), 7.57(1H, m), 7.59(1H, m),7.83(1H, m) ppm. Anal. Calcd for C₁₆H₁₉N₅O₄1.2 H₂O.1.1TFA: C, 44.23; H,4.63; N, 14.17. Found: C, 43.95; H, 4.39; N, 14.37.

EXAMPLE 9

[0304]

[0305] To the mixture of 4 (730 mg, 1.73 mmol) and pentafluorophenol(637 mg, 3.46 mmol) in DMF (5.0 ml) was addedO-Benzotriazole-N,N,N′,N′-tetramethyl-uronium-hexafluoro-phosphate(HBTU) (656 mg, 1.73 mmol). The mixture was stirred for two hours atroom temperature. To this resulting mixture was added a solution of 2(359 mg, 2.60 mmol) and N-methyl morpholine (263 mg, 2.6 mmol) in DMF(2.0 ml). After the mixture was stirred for 16 hours at roomtemperature, it was quenched with water and the solvents were allowed toevaporated under reduced pressure. The residue was purified throughpreparative HPLC (C-18 column, eluted with water/acetonitrile) toisolate desired product 5 (600 mg) as a white amorphous solid. ¹HNMR(400MHz, DMSO-d6, vs TMS) δ2.53(1H, dd, J=3.36, 3.34 Hz), 2.96(1H, dd,J=8.19, 8.30 Hz), 3.38(2H, dd, J=3.35, 3.36 Hz), 3.51(2H, dd, J=2.88,2.88 Hz), 4.08(2H, s); 4.28(2H, m), 4.56(1H, dd, J=9.55, 9.56 Hz),4.63(1H, m), 8.23(1H, m), 8.66(1H, d, J=2.30 Hz), 8.95(1H, d,J=1.66)ppm. Anal. Calcd for C₁₆H₂₀N₆O₅.2 H₂O.1.6TFA, C, 38.77; H, 4.34;N, 14.13. Found: C, 38.78; H, 4.32; N, 14.06. EXAMPLES 10, 11, 12, 13,14, 15, 16, 17, 18 and 19 were prepared according to the followinggeneral synthetic scheme:

[0306] General procedures: Proton magnetic resonance spectra wererecorded at 300 MHz and 400 MHz Varian spectrometers. High resolutionMass was performed by Analytical Lab of Searle. Commercial reagents wereused upon receipt without further purification. Reaction were carriedout under nitrogen unless otherwise noted. Compound 2i(R=p-fluorophenyl) was obtained from outside service company. Compound 1(racemic) were provided by Carbogen.

[0307] General procedure for the preparation of3-N-t-Boc-amino-4-hydroxyl-4-R-butyric acid benzyl ester:

[0308] Method A:

[0309] A solution of 5.2 g (16.94 mmol) aldehyde 1 in 130 mL anhydrousdiethylether was cooled to −30° C. Solution turned cloudy while cooling.To this cold suspension was slowly added 16 mL 3.0M diethylethersolution of methylmagnesium bromide along the side of the flask. Theresulting mixture was stirred at −30° C. for 10 minutes then warmed upto 0° C. for one and a half hour then room temperature for 30 minutes.After that, the reaction was poured in to a separation funnel containingice water. The aqueous phase was extracted with diethylether. Theorganic layer was washed successively with 1N aqueous HCl, saturatedaqueous NaHCO₃ and brine. Then it was dried over sodium sulfate,filtered and concentrated to give a yellowish oil which was useddirectly in next step without purification.

[0310] Method B:

[0311] To a solution of 4.2 g (13.68 mmol) aldehyde 1 in 68.4 mLanhydrous THF at −50° C. was added 17.1 mL THF solution ofi-butylmagnesium chloride (34.2 mmol) dropwise. The resulting solutionwas slowly warmed up to −20° C. over a period of two hours, then it waswarmed up to 0° C. for one hour. After reaction, the mixture was pouredon to ice water and was extracted with ethylacetate. The organic layerwas washed successively with 1N aqueous HCl(×2), saturated aqueousNaHCO₃ and brine, then dried over Na₂SO₄, filtered and concentrated togive a yellowish oil.

[0312] Method C:

[0313] 3.5 g (25.68 mmol) ZnCl₂ powder was dissolved in 30 mL THF andthe solution was cooled to −10° C. Ethynylmagnesium bromide (51.79 mL,0.5 M) in THF was slowly added along the side of the flask. Theresulting mixture was stirred at −10° C. for an additional 10 minutesthen warmed up to room temperature for 30 minutes before it was cooledto −40° C. The cold solution was then charged with aldehyde 1 (3.18 g,10.358 mmol) in 15 mL THF and stirred at −40° C. for 30 minutes thenwarmed up to 0° C. for two hours. After stirring at room temperature foranother one hour, the reaction was poured on to ice water and extractedwith ethylacetate. The organic layer was washed successively with 1Naqueous HCl(×2), saturated aqueous NaHCO₃ and brine, then dried overNa₂SO₄, filtered and concentrated to give a yellowish oil. This crudeoil was used directly in next step without further purification.

[0314] Preparation of compound 21:

[0315] To the cold suspension of 1.51 g (5.79 mmol)2-t-butoxy-2-oxoethylzinc bromide in 29 mL THF at −40° C. was added 2.5mL THF solution of 593 mg (1.93 mmol) aldehyde 1. The mixture wasstirred at −40° C. for one hour then the cooling bath was replaced byice water bath and the mixture was slowly warmed up to 5° C. over 18hours. After warmed up to room temperature for one hour, the mixture waspoured into a separation funnel containing IN aqueous HCl. The aqueouslayer was extracted with ethylacetate. The organic phase was washedsuccessively with 1N aqueous HCl (×2), saturated aqueous NaHCO₃ andbrine, then dried over Na₂SO₄, filtered and concentrated to give ayellowish oil which was used directly in next step.

[0316] Preparation of compound 2k:

[0317] A solution of 2.56 g (8.3 mmol) of aldehyde 1 in 20 mL THF wascooled to −40° C. To this cold solution was added 25 mL 0.5 M solutionof Trimethyl(trifluoromethyl)silane (TMSCF₃) in THF followed by 0.5 mLTHF solution of TBAF (0.5 mmol). The mixture was slowly warmed up to−10° C. over a period of two hours. Cooling bath was removed and thesolution was allowed to warm up to room temperature for 30 minutes.After diluted with ethylacetate, the organic phase was washed withbrine, dried over sodium sulfate, filtered and concentrated to give abrownish red oily residue which was used directly in next step.

[0318] Preparation of 3,5-dichloromagnesium bromide:

[0319] A three-necked round bottom flask equipped with condenser wasflame dried and cooled to room temperature. Into this flask was placed1.65 g magnesium turnings, 45 mL anhydrous diethylether and 10.05 g1-bromo-3,5-dichlorobenzene. The mixture was cooled to 0° C. and onechip of iodine was added. The cooling bath was removed and the mixturewas slowly warmed up to 50° C. using a water bath. When the bubblingstopped, another 5.1 g of 1-bromo-3,5-dichlorobenzene was added intothis mixture followed by another chip of iodine. The mixture was heatedto 60° C. and kept at 50° C. to 60° C. till all magnesium turnings hasdissolved. The solution was then cooled to room temperature and useddirectly.

[0320] General procedure for the preparation compound 3a:

[0321] The crude mixture of 2a prepared from previous step was treatedwith 30 mL of 1N hydrogen chloride in acetic acid at room temperature.The progress of reaction was monitored by TLC. After about 30 minutes,reaction went to completion. Solvents were removed in vaco and theresidue was co-evaporated with ethylacetate three times. The resultingbrownish oil was partitioned between water and ethylacetate. The organicphase was disposed of. The aqueous layer was frozen dried to give ayellow solid which was used directly in next step without furtherpurification.

[0322] Compound 3b-31: compounds 3b -31 were prepared following thegeneral procedure for the preparation of compound 3a respectively.

EXAMPLE 10

[0323]

[0324] General procedure for the preparation of compound 5a:

[0325] To a suspension of 4.85 g crude 3a and 4.6 g of compound 4(prepared using similar procedure described in EXAMPLE 6, step 6a, 6b,6c) in 15 mL DMA at room temperature was added 608 mg HOBT followed by2.58 mL N,N-diisopropylcarbodiimide. The resulting mixture was stirredat room temperature overnight to give a brown solution. To this solutionwas added 4.7 g LiOH H₂O and 5 mL of water. Ethanol was added into themixture till a clear solution was obtained. The progress of reaction wasmonitored by Mass spectrometry and analytical HPLC. After about 40minutes, saponification completed. The basic solution was acidified topH=1 with trifluoroacetic acid and purified by reverse phase preparativeHPLC. Those fractions having molecular weight of compound 5a werecombined and frozen dried to give a white flake. The white flake wasthen treated with neat trifluoroacetic acid at room temperature. Themixture was purified again by reverse phase preparative HPLC to givecompound 5a as a white flake. ¹H NMR (400 MHZ, CD3OD): δ (ppm) 1.29 (d,J=6.4 Hz, 3H), 2.46 (dd, J=2.8, 18.0 Hz, 1H), 3.02 (dd, J=8.0, 18.0 Hz,1H), 3.32(dd, J=3.2, 12.0 Hz, 2H), 3.44(dd, J=3.2, 12.0 Hz, 2H), 4.01(t, J=4.4 Hz, 2H), 4.21-4.23 (m, 1H), 4.64-4.70 (m, 1H), 4.75-4.78 (m,1H), 6.82 (dd, J=2.0, 2.0 Hz, 1H), 7.17 (dd, J=1.6, 1.6 Hz, 1H), 7.20(dd, J=2.0, 2.0 Hz, 1H); MS (M+H): 432.2.

EXAMPLE 11

[0326]

[0327] The title compound was prepared following the general procedurefor the preparation of compound EXAMPLE 10. ¹H NMR (300 MHZ, CD₃OD): δ(ppm) 2.46-2.57 (m, 2H), 2.57 (dd, J=5.7, 18.0 Hz, 1H), 2.99 (dd, J=8.4,18.0 Hz, 1H), 3.34 (dd, J=3.3, 12.6 Hz, 2H), 3.49 (dd, J=3.0, 12.6 Hz,2H), 4.02 (t, J=3.6 Hz, 2H), 4.24-4.28 (m, 1H), 4.38-4.49 (m, 2H),5.11-5.27 (m, 2H), 5.80-5.94 (m, 1H), 6.87 (dd, J=2.1, 2.1 Hz, 1H), 7.21(dd, J=2.1, 2.1 Hz, 1H), 7.24 (dd, J=2.1, 2.1 Hz, 1H); Theoretical MS(M+H): 406.1727; Found: 406.1716.

EXAMPLE 11

[0328]

[0329] The title compound was prepared following the general procedurefor the preparation of compound EXAMPLE 10. ¹H NMR (400 MHZ, CD₃OD): δ(ppm) 0.87 (d, J=6.4 Hz, 3H), 1.09 (d, J=6.8 Hz, 3H), 1.94-1.99 (m, 1H),2.41 (d, J=18.0, 1H), 3.05 (dd, J=7.2, 18.0 Hz, 1H), 3.30 (dd, J=3.6,12.4 Hz, 2H), 3.44 (dd, J=2.4, 12.4 Hz, 2H), 3.98 (t, J=4.4 Hz, 2H),4.13-4.17 (m, 1H), 4.21-4.23 (m, 1H), 4.74-4.80 (m, 1H), 6.82 (dd,J=2.0, 2.0 Hz, 1H), 7.16 (dd, J=2.0, 2.0 Hz, 1H), 7.19 (dd, J=2.0, 2.0Hz, 1H); Theoretical MS (M+H): 434.2040; Found: 434.2023

EXAMPLE 12

[0330]

[0331] The title compound was prepared following the general procedurefor the preparation of compound EXAMPLE 10. ¹H NMR (400 MHZ, CD₃OD): δ(ppm) 0.94-0.97 (m, 6H), 1.37-1.43 (m, 1H), 1.59-1.66 (m, 1H), 1.73-1.78(m, 1H), 2.42 (dd, J=1.6, 17.6 Hz, 1H), 3.03 (dd, J=7.6, 17.6 Hz, 1H),3.30 (dd, J=3.6, 12.4 Hz, 2H), 3.44 (dd, J=2.4, 12.4 Hz, 2H), 3.99 (brs,1H), 4.21-4.23 (m, 1H), 4.69-4.72 (m, 2H), 6.83 (dd, J=2.4, 2.4 Hz, 1H),7.17 (dd, J=1.6, 1.6 Hz, 1H), 7.20 (dd, J=1.6, 1.6 Hz, 1H); TheoreticalMS (M+H): 448.2196; Found: 448.2205.

EXAMPLE 13

[0332]

[0333] The title compound was prepared following the general procedurefor the preparation of compound EXAMPLE 10. ¹H NMR (400 MHZ, CD₃OD): δ(ppm) 2.58 (dd, J=6.0, 17.6 Hz, 1H), 2.93 (dd, J=8.0, 17.6 Hz, 1H), 3.22(2s, 1H), 3.31 (dd, J=3.6, 12.4 Hz, 2H), 3.44 (dd, J=2.8, 12.4 Hz, 2H),4.02 (d, J=17.2, 1H), 4.09 (d, J=17.2 Hz, 1H), 4.21-4.23 (m, 1H),4.80-4.90 (obscure m, 1H), 5.39 & 5.41 (2d, J=2.4 Hz, 1H), 6.83 (dd,J=2.4, 2.4 Hz, 1H), 7.17 (dd, J=1.6, 1.6 Hz, 1H), 7.19 (dd, J=1.6, 1.6Hz, 1H); Theoretical MS (M+H): 416.1570; Found: 416.1579

EXAMPLE 14

[0334]

[0335] The title compound was prepared following the general procedurefor the preparation of compound EXAMPLE 10, except no saponification wascarried out. After coupling with compound 4, the mixture was treatedwith trifluoroacetic acid and water. When lactonization has completed,the resulting mixture was purified by reverse phase preparative HPLC. ¹HNMR (400 MHZ, CD₃OD): δ (ppm) 0.89 (t, J=7.2 Hz, 3H), 1.28-1.36 (m, 6H),1.54-1.74 (m, 2H), 2.43 (dd, J=2.4, 18.0 Hz, 1H), 3.02 (dd, J=8.0, 18.0Hz, 1H), 3.30 (dd, J=3.6, 12.4 Hz, 2H), 3.44 (dd, J=2.8, 12.4 Hz, 2H),3.99 (brs, 2H), 4.21-4.23 (m, 1H), 4.56-4.61 (m, 1H), 4.69-4.74 (m, 1H),6.83 (t, J=2.0 Hz, 1H), 7.17 (t, J=1.6 Hz, 1H), 7.20 (t, J=1.6 Hz, 1H);Theoretical MS (M+H): 462.2353; Found: 462.2352.

EXAMPLE 15

[0336]

[0337] The title compound was prepared following the general procedurefor the preparation of compound EXAMPLE 10. ¹H NMR (400 MHZ, CD₃OD): δ(ppm) 0.88 (t, J=6.8 Hz, 3H), 1.27-1.70 (m, 18H), 2.43 (dd, J=2.0, 17.6Hz, 1H), 3.02 (dd, J=8.0, 17.6 Hz, 1H), 3.30 (dd, J=3.6, 12.4 Hz, 2H),3.44 (dd, J=2.8, 12.4 Hz, 2H), 3.99 (dd, J=6.8, 6.8 Hz, 2H), 4.21-4.23(m, 1H), 4.54-4.62 (m, 1H), 4.68-4.74 (m, 1H), 6.82 (t, J=2.0 Hz, 1H),7.16 (t, J=1.6 Hz, 1H), 7.19 (t, J=1.6 Hz, 1H); Theoretical MS (M+H):532.3135; Found: 532.3146.

EXAMPLE 16

[0338]

[0339] The title compound was prepared following the general procedurefor the preparation of compound EXAMPLE 10, except no saponification wascarried out. After coupling with compound 4, the mixture was treatedwith trifluoroacetic acid and water. When lactonization has completed,the resulting mixture was purified by reverse phase preparative HPLC. ¹HNMR (400 MHZ, CD₃OD): δ (ppm) 2.64 (dd, J=5.2, 18.0 Hz, 1H), 2.99 (dd,J=8.4, 18.0 Hz, 1H), 3.30 (dd, J=3.6, 12.4 Hz, 2H), 3.44 (dd, J=2.4,12.4 Hz, 2H), 3.99 (d, J=16.4 Hz, 1H), 4.04 (d, J=16.4 Hz, 1H),4.21-4.24 (m, 1H), 4.50-4.55 (m, 1H), 5.44 (d, J=4.4, 1H), 6.83 (t,J=2.4 Hz, 1H), 7.17 (t, J=2.0 Hz, 1H), 7.21 (t, J=2.4 Hz, 1H), 7.25-7.43(m, 5H); Theoretical MS (M+H): 468.1883; Found: 468.1880.

EXAMPLE 17

[0340]

[0341] The title compound was prepared following the general procedurefor the preparation of compound EXAMPLE 10. ¹H NMR (400 MHZ, CD₃OD): δ(ppm) 2.61 (dd, J=2.8, 17.6 Hz, 1H), 3.17 (dd, J=8.4, 17.6 Hz, 1H), 3.30(dd, J=3.6, 12.8 Hz, 2H), 3.44 (dd, J=2.8, 12.8 Hz, 2H), 3.52 (d, J=16.4Hz, 1H), 3.76 (d, J=16.4 Hz, 1H), 4.21-4.23 (m,1H), 4.94-4.97 (m, 1H),5.75 (d, J=5.6 Hz, 1H), 6.81 (t, J=2.4 Hz, 1H), 7.05-7.13 (m, 4H),7.28-7.32 (m, 2H); Theoretical MS (M+H): 486.1789;Found: 486.1801.

EXAMPLE 18

[0342]

[0343] The title compound was prepared following the general procedurefor the preparation of compound EXAMPLE 10. Diastereomer a: ¹H NMR (400MHZ, CD₃OD): δ (ppm) 2.61 (dd, J=2.0, 18.0 Hz, 1H), 3.19 (dd, J=8.0,18.0 Hz, 1H), 3.30 (dd, J=3.6, 12.4 Hz, 2H), 3.44 (dd, J=2.4, 12.4 Hz,2H), 3.53 (d, J=16.4 Hz, 1H), 3.78 (d, J=16.4 Hz, 1H), 4.21-4.23 (m,1H), 4.96-5.02 (m, 1H), 5.73 (d, J=5.6 Hz, 1H), 6.80 (t, J=2.0 Hz, 1H),7.09 (t, J=2.0 Hz, 1H), 7.13 (t, J=2.0 Hz, 1H), 7.27-7.28 (m, 2H), 7.37(t, J=2.0 Hz, 1H). Diastereomer b): ¹H NMR (400 MHZ, CD₃OD): δ (ppm)2.65 (dd, J=5.6, 18.0 Hz, 1H), 3.0 (dd, J=8.4, 18.0 Hz, 1H), 3.30 (dd,J=3.6, 12.4 Hz, 2H), 3.44 (dd, J=2.4, 12.4 Hz, 2H), 4.01 (brs, 2H),4.21-4.23 (m, 1H), 4.48-4.53 (m, 1H), 5.40 (d, J=4.8 Hz, 1H), 6.83 (t,J=2.0 Hz, 1H), 7.19 (t, J=2.0 Hz, 1H), 7.22 (t, J=2.0 Hz, 1H), 7.43(brs, 3H).

EXAMPLE 19

[0344]

[0345] The title compound was prepared following the general procedurefor the preparation of compound EXAMPLE 10, except no saponification wascarried out. After coupling with compound 4, the mixture was treatedwith trifluoroacetic acid and water. When lactonization has completed,the resulting mixture was purified by reverse phase preparative HPLC. ¹HNMR (400 MHZ, CD₃OD): δ (ppm) 2.58 (dd, J=6.0, 18.0 Hz, 1H), 2.73 (dd,J=7.6, 16.8 Hz, 1H), 2.88 (dd, J=4.4, 16.8 Hz, 1H), 3.01 (dd, J=8.8,18.0 Hz, 1H), 3.31 (dd, J=3.6, 12.4 Hz, 2H), 3.44 (dd, J=2.4, 12.4 Hz,2H), 4.00 (brs, 2H), 4.20-4.24 (m, 1H), 4.45-4.50 (m, 1H), 4.65-4.70 (m,1H), 6.83 (t, J=2.0 Hz, 1H), 7.17 (t, J=2.0 Hz, 1H), 7.2 (t, J=2.0 Hz,1H).

[0346] Activity of the compounds of the present invention can be testedin the following assays. Compounds of the present invention antagonizethe α_(v)β₃ integrin with an IC₅₀ of 0.1 nM to 100 μM in the 293-cellassay. Similarly these compounds also antagonized the α_(v)β₅ integrinwith an IC₅₀ of <50 μM in the cell adhesion assay.

Vitronectin Adhesion Assay

[0347] Human vitronectin receptors α_(v)β₃ and α_(v)β₅ are purified fromhuman placenta as previously described [Pytela et al., Methods inEnzymology, 144:475-489 (1987)]. Human vitronectin is purified fromfresh frozen plasma as previously described [Yatohgo et al., CellStructure and Function, 13:281-292 (1988)]. Biotinylated humanvitronectin is prepared by coupling NHS-biotin from Pierce ChemicalCompany (Rockford, Ill.) to purified vitronectin as previously described[Charo et al., J. Biol. Chem., 266(3):1415-1421 (1991)]. Assay buffer,OPD substrate tablets, and RIA grade BSA are obtained from Sigma (St.Louis, Mo.). Anti-biotin antibody is obtained from Sigma (St. Luois,Mo.). Nalge Nunc-Immuno microtiter plates were obtained from NalgeCompany (Rochester, N.Y.).

[0348] This assay is essentially the same as previously reported [Niiyaet al., Blood, 70:475-483 (1987)]. The purified human vitronectinreceptors α_(v)β₃ and α_(v)β₅ are diluted from stock solutions to 1.0μg/mL in Tris-buffered saline containing 1.0 mM Ca⁺⁺, Mg⁺⁺, and Mn⁺⁺, pH7.4 (TBS⁺⁺⁺). The diluted receptors are immediately transferred to NalgeNunc-Immuno microtiter plates at 100 μL/well (100 ng receptor/well). Theplates are sealed and incubated overnight at 4° C. to allow thereceptors to bind to the wells. All remaining steps are at roomtemperature. The assay plates are emptied and 200 μL of 1% RIA grade BSAin TBS⁺⁺⁺ (TBS⁺⁺⁺/BSA) are added to block exposed plastic surfaces.Following a 2 hour incubation, the assay plates are washed with TBS⁺⁺⁺using a 96 well plate washer. Logarithmic serial dilution of the testcompound and controls are made starting at a stock concentration of 2 mMand using 2 nM biotinylated vitronectin in TBS⁺⁺⁺/BSA as the diluent.This premixing of labeled ligand with test (or control) ligand, andsubsequent transfer of 50 μL aliquots to the assay plate is carried outwith a CETUS Propette robot; the final concentration of the labeledligand is 1 nM and the highest concentration of test compound is1.0×10⁻⁴ M. The competition occurred for two hours after which all wellsare washed with a plate washer as before. Affinity purified horseradishperoxidase labeled goat anti-biotin antibody is diluted 1:2000 inTBS⁺⁺⁺/BSA and 125 μL is added to each well. After 45 minutes, theplates are washed and incubated with OPD/H₂O₂ substrate in 100 mM/LCitrate buffer, pH 5.0. The plate is read with a microtiter plate readerat a wavelength of 450 nm and when the maximum-binding control wellsreached an absorbance of about 1.0, the final A₄₅₀ are recorded foranalysis. The data are analyzed using a macro written for use with theEXCEL spreadsheet program. The mean, standard deviation, and % CV weredetermined for duplicate concentrations. The mean A₄₅₀ values arenormalized to the mean of four maximum-binding controls (no competitoradded)(B-MAX). The normalized values are subjected to a four parametercurve fit algorithm [Rodbard et al., Int. Atomic Energy Agency, Vienna,pp 469 (1977)], plotted on a semi-log scale, and the computedconcentration corresponding to inhibition of 50% of the maximum bindingof biotinylated vitronectin (IC₅₀) and corresponding R² is reported forthose compounds exhibiting greater than 50% inhibition at the highestconcentration tested; otherwise the IC₅₀ is reported as being greaterthan the highest concentration tested.

Purified IIb/IIIa Receptor Assay

[0349] Human fibrinogen receptor (α_(v)β₃) is purified from outdatedplatelets. (Pytela, R., Pierschbacher, M. D., Argraves, S., Suzuki, S.,and Rouslahti, E. “Arginine-Glycine-Aspartic acid adhesion receptors”,Methods in Enzymology 144(1987):475-489.) Human vitronectin is purifiedfrom fresh frozen plasma as described in Yatohgo, T., Izumi, M.,Kashiwagi, H., and Hayashi, M., “Novel purification of vitronectin fromhuman plasma by heparin affinity chromatography,” Cell Structure andFunction 13(1988):281-292. Biotinylated human vitronectin is prepared bycoupling NHS-biotin from Pierce Chemical Company (Rockford, Ill.) topurified vitronectin as previously described. (Charo, I. F., Nannizzi,L., Phillips, D. R., Hsu, M. A., Scarborough, R. M., “Inhibition offibrinogen binding to GP IIb/IIIa by a GP IIIa peptide”, J. Biol. Chem.266(3)(1991): 1415-1421.) Assay buffer, OPD substrate tablets, and RIAgrade BSA are obtained from Sigma (St. Louis, Mo.). Anti-biotin antibodyis obtained from Sigma (St. Louis, Mo.). Nalge Nunc-Immuno microtiterplates are obtained from (Rochester, N.Y.). ADP reagent is obtained fromSigma (St. Louis, Mo.).

[0350] This assay is essentially the same reported in Niiya, K., Hodson,E., Bader, R., Byers-Ward, V. Koziol, J. A., Plow, E. F. and Ruggeri, Z.M., “Increased surface expression of the membrane glycoprotein IIb/IIIacomplex induced by platelet activation: Relationships to the binding offibrinogen and platelet aggregation”, Blood 70(1987):475-483. Thepurified human fibrinogen receptor (α_(v)β₃) is diluted from stocksolutions to 1.0 μg/mL in Tris-buffered saline containing 1.0 mM Ca⁺⁺,Mg⁺⁺, and Mn⁺⁺, pH 7.4 (TBS⁺⁺⁺). The diluted receptor is immediatelytransferred to Nalge Nunc-Immuno microtiter plates at 100 μL/well (100ng receptor/well). The plates are sealed and incubated overnight at 4°C. to allow the receptors to bind to the wells. All remaining steps areat room temperature. The assay plates are emptied and 200 μL of 1% RIAgrade BSA in TBS⁺⁺⁺ (TBS⁺⁺⁺/BSA) are added to block exposed plasticsurfaces. Following a 2 hour incubation, the assay plates are washedwith TBS⁺⁺⁺ using a 96 well plate washer. Logarithmic serial dilution ofthe test compound and controls are made starting at a stockconcentration of 2 mM and using 2 nM biotinylated vitronectin inTBS⁺⁺⁺/BSA as the diluent. This premixing of labeled ligand with test(or control) ligand, and subsequent transfer of 50 μL aliquots to theassay plate is carried out with a CETUS Propette robot; the finalconcentration of the labeled ligand is 1 nM and the highestconcentration of test compound is 1.0×10⁻⁴ M. The competition occurredfor two hours after which all wells are washed with a plate washer asbefore. Affinity purified horseradish peroxidase labeled goatanti-biotin antibody is diluted 1:2000 in TBS⁺⁺⁺/BSA and 125 μL areadded to each well. After 45 minutes, the plates are washed andincubated with ODD/H₂O₂ substrate in 100 mM/L citrate buffer, pH 5.0.The plate was read with a microtiter plate reader at a wavelength of 450nm and when the maximum-binding control wells reached an absorbance ofabout 1.0, the final A₄₅₀ are recorded for analysis. The data areanalyzed using a macro written for use with the EXCELJ spreadsheetprogram. The mean, standard deviation, and % CV are determined forduplicate concentrations. The mean A₄₅₀ values are normalized to themean of four maximum-binding controls (no competitor added)(B-MAX). Thenormalized values are subjected to a four parameter curve fit algorithm,[Robard et al., Int. Atomic Energy Agency, Vienna, pp 469 (1977)],plotted on a semi-log scale, and the computed concentrationcorresponding to inhibition of 50% of the maximum binding ofbiotinylated vitronectin (IC₅₀) and corresponding R² was reported forthose compounds exhibiting greater than 50% inhibition at the highestconcentration tested; otherwise the IC₅₀ is reported as being greaterthan the highest concentration tested.β-[[2-[[5-[(aminoiminomethyl)amino]-1-oxopentyl]amino]-1-oxoethyl]amino]-3-pyridinepropanoicacid [U.S. Pat. No. 5,602,155 Example 1] which is a potent α_(v)β₃antagonist (IC₅₀ in the range 3-10 nM) is included on each plate as apositive control.

Human Platelet Rich Plasma Assays

[0351] Healthy aspirin free donors are selected from a pool ofvolunteers. The harvesting of platelet rich plasma and subsequent ADPinduced platelet aggregation assays are performed as described inZucker, M. B., “Platelet Aggregation Measured by the PhotometricMethod”, Methods in Enzymology 169(1989):117-133. Standard venipuncturetechniques using a butterfly allowed the withdrawal of 45 mL of wholeblood into a 60 mL syringe containing 5 mL of 3.8% trisodium citrate.Following thorough mixing in the syringe, the anti-coagulated wholeblood is transferred to a 50 mL conical polyethylene tube. The blood iscentrifuged at room temperature for 12 minutes at 200×g to sedimentnon-platelet cells. Platelet rich plasma is removed to a polyethylenetube and stored at room temperature until used. Platelet poor plasma isobtained from a second centrifugation of the remaining blood at 2000×gfor 15 minutes. Platelet counts are typically 300,000 to 500,000 permicroliter. Platelet rich plasma (0.45 mL) is aliquoted into siliconizedcuvettes and stirred (1100 rpm) at 37° C. for 1 minute prior to adding50 uL of pre-diluted test compound. After 1 minute of mixing,aggregation is initiated by the addition of 50 uL of 200 uM ADP.Aggregation is recorded for 3 minutes in a Payton dual channelaggregometer (Payton Scientific, Buffalo, N.Y.). The percent inhibitionof maximal response (saline control) for a series of test compounddilutions is used to determine a dose response curve. All compounds aretested in duplicate and the concentration of half-maximal inhibition(IC₅₀) is calculated graphically from the dose response curve for thosecompounds which exhibited 50% or greater inhibition at the highestconcentration tested; otherwise, the IC₅₀ is reported as being greaterthan the highest concentration tested.

Cell Assays for Potency and Selectivity

[0352] While the β₃ subunit of α_(v)β₃ is only known to complex withα_(v) or α_(IIb), the α_(v) subunit complexes with multiple β subunits.The three α_(v) integrins most homologous with α_(v)β₃ are α_(v)β₁,α_(v)β₅ and α_(v)β₆, with 43%, 56% and 47% amino acid identity in the βsubunits, respectively. To evaluate the selectivity of compounds betweenthe integrins α_(v)β₃ and α_(v)β₆, cell-based assays were establishedusing the 293 human embryonic kidney cell line. 293 cells expressα_(v)β₁, but little to no detectable α_(v)β₃ or α_(v)β₆. cDNAs for β₃and β₆ were transfected separately into 293 cells to generate 293-β3 and293-β6 cells, respectively. High surface expression of α_(v)β₃ andα_(v)β₆ was confirmed by flow cytometry. Conditions were established foreach cell line in which cell adhesion to immobilized human vitronectinwas mediated by the appropriate integrin, as determined by a panel ofintegrin-specific, neutralizing monoclonal antibodies. Briefly, cellswere incubated with inhibitor in the presence of 200 uM Mn²⁺, allowed toadhere to immobilized vitronectin, washed, and adherent cells aredetected endogenous alkaline phosphatase and para-nitrophenyl phosphate.An 8-point dose-response curve using either 10-fold or 3-fold dilutionsof compound was evaluated by fitting a four-parameter logistic,nonlinear model (using SAS).

[0353] To evaluate compound potency for membrane-bound α_(v)β₆ anadditional cell-based adhesion assay was established using the HT-29human colon carcinoma cell line. High surface expression of α_(v)β₆ onHT-29 cells was confirmed by flow cytometry. Conditions were establishedin which cell adhesion to immobilized human latency associated peptide(LAP) was mediated by the α_(v)β₆, as determined by a panel ofintegrin-specific, neutralizing monoclonal antibodies. Briefly, cellswere incubated with inhibitor in the presence of 200 uM Mn²⁺, allowed toadhere to immobilized LAP, washed, and adherent cells are detected byquantifying endogenous alkaline phosphatase using para-nitrophenylphosphate. An 8-point dose-response curve using either 10-fold or 3-folddilutions of compound was evaluated by fitting a four-parameterlogistic, nonlinear model (using SAS). The compounds evaluated wererelatively ineffective at inhibition of α_(v)β₆-mediated cell adhesion.The selective antagonism of the α_(v)β₃ integrin is viewed as desirablein this class of compounds, as α_(v)β₆ may also play a role in normalphysiological processes of tissue repair and cellular turnover thatroutinely occur in the skin and pulmonary tissues.

What is claimed is:
 1. A compound of Formula I

Y is selected from the group consisting of N—R¹, O, and S; y and z areindependently selected from an integer selected from 0, 1, 2 and 3; A isN or C; R¹ is selected from the group consisting of H, alkyl, aryl,hydroxy, alkoxy, cyano, nitro, amino, alkenyl, alkynyl, amido,alkylcarbonyl, arylcarbonyl, alkoxycarbonyl, aryloxycarbonyl,haloalkylcarbonyl, haloalkoxycarbonyl, alkylthiocarbonyl,arylthiocarbonyl, acyloxymethoxycarbonyl, alkyl optionally substitutedwith one or more substituent selected from lower alkyl, halogen,hydroxyl, haloalkyl, cyano, nitro, carboxyl, amino, alkoxy, aryl or aryloptionally substituted with one or more halogen, haloalkyl, lower alkyl,alkoxy, cyano, alkylsulfonyl, alkylthio, nitro, carboxyl, amino,hydroxyl, sulfonic acid, sulfonamide, aryl, fused aryl, monocyclicheterocycles, or fused monocyclic heterocycles, aryl optionallysubstituted with one or more substituent selected from halogen,haloalkyl, hydroxy, lower alkyl, alkoxy, methylenedioxy, ethylenedioxy,cyano, nitro, alkylthio, alkylsulfonyl, sulfonic acid, sulfonamide,carboxyl derivatives, amino, aryl, fused aryl, monocyclic heterocyclesand fused monocyclic heterocycle, monocyclic heterocycles, andmonocyclic heterocycles optionally substituted with one or moresubstituent selected from halogen, haloalkyl, lower alkyl, alkoxy,amino, nitro, hydroxy, carboxyl derivatives, cyano, alkylthio,alkylsulfonyl, sulfonic acid, sulfonamide, aryl or fused aryl; or R¹taken together with R⁸ forms a 4-12 membered dinitrogen containingheterocycle optionally substituted with one or more substituent selectedfrom the group consisting of lower alkyl, hydroxy, keto, alkoxy, halo,phenyl, amino, carboxyl or carboxyl ester, and fused phenyl; or R¹ takentogether with R⁸ forms a 5 membered heteroaromatic ring optionallysubstituted with one or more substituent selected from lower alkyl,phenyl and hydroxy; or R¹ taken together with R⁸ forms a 5 memberedheteroaromatic ring fused with a phenyl group; R⁸ (when not takentogether with R¹) and R⁹ are independently selected from the groupconsisting of H, alkyl, alkenyl, alkynyl, aralkyl, amino, alkylamino,hydroxy, alkoxy, arylamino, amido, alkylcarbonyl, arylcarbonyl,alkoxycarbonyl, aryloxy, aryloxycarbonyl, haloalkylcarbonyl,haloalkoxycarbonyl, alkylthiocarbonyl, arylthiocarbonyl,acyloxymethoxycarbonyl, cycloalkyl, bicycloalkyl, aryl, acyl, benzoyl,alkyl optionally substituted with one or more substituent selected fromlower alkyl, halogen, hydroxy, haloalkyl, cyano, nitro, carboxylderivatives, amino, alkoxy, thio, alkylthio, sulfonyl, aryl, aralkyl,aryl optionally substituted with one or more substituent selected fromhalogen, haloalkyl, lower alkyl, alkoxy, methylenedioxy, ethylenedioxy,alkylthio, haloalkylthio, thio, hydroxy, cyano, nitro, carboxylderivatives, aryloxy, amido, acylamino, amino, alkylamino, dialkylamino,trifluoroalkoxy, trifluoromethyl, sulfonyl, alkylsulfonyl,haloalkylsulfonyl, sulfonic acid, sulfonamide, aryl, fused aryl,monocyclic heterocycles, fused monocyclic heterocycles, aryl optionallysubstituted with one or more substituent selected from halogen,haloalkyl, lower alkyl, alkoxy, methylenedioxy, ethylenedioxy,alkylthio, haloalkylthio, thio, hydroxy, cyano, nitro, carboxylderivatives, aryloxy, amido, acylamino, amino, alkylamino, dialkylamino,trifluoroalkoxy, trifluoromethylsulfonyl, alkylsulfonyl, sulfonic acid,sulfonamide, aryl, fused aryl, monocyclic heterocycles, or fusedmonocyclic heterocycles, monocyclic heterocycles, monocyclicheterocycles optionally substituted with one or more substituentselected from halogen, haloalkyl, lower alkyl, alkoxy, aryloxy, amino,nitro, hydroxy, carboxyl derivatives, cyano, alkylthio, alkylsulfonyl,aryl, fused aryl, monocyclic and bicyclic heterocyclicalkyls, —SO₂R¹⁰wherein R¹⁰ is selected from the group consisting of alkyl, aryl andmonocyclic heterocycles, all optionally substituted with one or moresubstituent selected from the group consisting of halogen, haloalkyl,alkyl, alkoxy, cyano, nitro, amino, acylamino, trifluoroalkyl, amido,alkylaminosulfonyl, alkylsulfonyl, alkylsulfonylamino, alkylamino,dialkylamino, trifluoromethylthio, trifluoroalkoxy,trifluoromethylsulfonyl, aryl, aryloxy, thio, alkylthio, and monocyclicheterocycles; and

wherein R¹⁰ is defined as above; or NR⁸ and R⁹ taken together form a4-12 membered mononitrogen containing monocyclic or bicyclic ringoptionally substituted with one or more substituent selected from loweralkyl, carboxyl derivatives, aryl or hydroxy and wherein said ringoptionally contains a heteroatom selected from the group consisting ofO, N and S; or

wherein Y′ is selected from the group consisting of alkyl, cycloalkyl,bicycloalkyl, aryl, monocyclic heterocycles, alkyl optionallysubstituted with aryl which can also be optionally substituted with oneor more substituent selected from halo, haloalkyl, alkyl, nitro,hydroxy, alkoxy, aryloxy, aryl, or fused aryl, aryl optionallysubstituted with one or more substituent selected from halo, haloalkyl,hydroxy, alkoxy, aryloxy, aryl, fused aryl, nitro, methylenedioxy,ethylenedioxy, or alkyl, alkynyl, alkenyl, —S—R¹¹ and —OR¹¹ wherein R¹¹is selected from the group consisting of H, alkyl, aralkyl, aryl,alkenyl, and alkynyl, or R¹¹ taken together with R⁸ forms a 4-12membered mononitrogen and monosulfur or monooxygen containingheterocyclic ring optionally substituted with lower alkyl, hydroxy,keto, phenyl, carboxyl or carboxyl ester, and fused phenyl, or R¹¹ takentogether with R⁸ is thiazole, oxazole, benzoxazole, or benzothiazole; R⁸is defined as above; or Y¹ (when Y¹ is carbon) taken together with R⁸forms a 4-12 membered mononitrogen or dinitrogen containing ringoptionally substituted with alkyl, aryl, keto or hydroxy; or

wherein R¹ and R⁸ taken together form a 5-8 membered dinitrogencontaining heterocycle optionally substituted with one or moresubstituent selected from the group consisting of lower alkyl, hydroxy,keto, phenyl, or carboxyl derivatives; and R⁹ is selected from the groupconsisting of alkylcarbonyl, arylcarbonyl, alkoxycarbonyl,aryloxycarbonyl, haloalkylcarbonyl, haloalkoxycarbonyl,alkylthiocarbonyl, arylthiocarbonyl, or acyloxymethoxycarbonyl; or

wherein R¹ and R⁸ taken together form a 5-8 membered dinitrogencontaining heterocycle optionally substituted with hydroxy, keto,phenyl, or alkyl; and R⁹ are both selected from the group consisting ofalkylcarbonyl, arylcarbonyl, alkoxycarbonyl, aryloxycarbonyl,haloalkylcarbonyl, haloalkoxycarbonyl, alkylthiocarbonyl,arylthiocarbonyl and acyloxymethoxycarbonyl; R², R³ and R⁴ areindependently selected from one or more substituent selected fromthegroup consisting of H, alkyl, hydroxy, alkoxy, aryloxy, halogen, haloalkyl, haloalkoxy, nitro, amino, alkylamino, acylamino, dialkylamino,cyano, alkylthio, alkylsulfonyl, carboxyl derivatives, trihaloacetamide,acetamide, aryl, fused aryl, cycloalkyl, thio, monocyclic heterocycles,fused monocyclic heterocycles, and X, wherein X is defined above; R⁵, R⁶and R⁷ are independently selected from the group consisting of hydrogen,alkyl, alkenyl, alkynyl, aryl, carboxyl derivatives, haloalkyl,cycloalkyl, monocyclic heterocycles, monocyclic heterocycles optionallysubstituted with alkyl, halogen, haloalkyl, cyano, hydroxy, aryl, fusedaryl, nitro, alkoxy, aryloxy, alkylsulfonyl, arylsulfonyl, sulfonamide,thio, alkylthio, carboxyl derivatives, amino, amido, alkyl optionallysubstituted with one or more of halo, haloalkyl, hydroxy, alkoxy,aryloxy, thio, alkylthio, alkynyl, alkenyl, alkyl, arylthio,alkylsulfoxide, alkylsulfonyl, arylsulfoxide, arylsulfonyl, cyano,nitro, amino, alkylamino, dialkylamino, alkylsulfonamide,arylsulfonamide, acylamide, carboxyl derivatives, sulfonamide, sulfonicacid, phosphonic acid derivatives, phosphinic acid derivatives, aryl,arylthio, arylsulfoxide, or arylsulfone all optionally substituted onthe aryl ring with halo, alkyl, haloalkyl, cyano, nitro, hydroxy,carboxyl derivatives, alkoxy, aryloxy, amino, alkylamino, dialkylamino,amido, aryl, fused aryl, monocyclic heterocycles, and fused monocyclicheterocycles, monocyclic heterocyclicthio, monocyclicheterocyclicsulfoxide, and monocyclic heterocyclic sulfone, which can beoptionally substituted with halo, haloalkyl, nitro, hydroxy, alkoxy,fused aryl, or alkyl, alkylcarbonyl, haloalkylcarbonyl, andarylcarbonyl, aryl optionally substituted in one or more positions withhalo, haloalkyl, alkyl, alkoxy, aryloxy, methylenedioxy, ethylenedioxy,alkylthio, haloalkylthio, thio, hydroxy, cyano, nitro, acyloxy, carboxylderivatives, carboxyalkoxy, amido, acylamino, amino, alkylamino,dialkylamino, trifluoroalkoxy, trifluoromethylsulfonyl, alkylsulfonyl,sulfonic acid, sulfonamide, aryl, fused aryl, monocyclic heterocyclesand fused monocyclic heterocycles; and all isomers, enantiomers,tautomers, racemates and polymorphs thereof.
 2. A compound according toclaim 1

wherein: z is 1; y is 0; R⁵ and R⁶ are H; R⁷=H; alkyl, haloalkyl,carboxyalkyl, alkenyl, alkynyl, and phenyl, optionally substituted withone or more halogen atom.
 3. A compound according to claim 1

wherein: R², R³, and R⁴ are H, OH, or haloalkyl;

Y is N—R¹ wherein R¹ is selected from the group consisting of H, alkyl,aryl, hydroxy, alkoxy, cyano, and nitro; R⁸ and R⁹ are H; or R¹ takentogether with R⁸ forms a 4-12 membered dinitrogen containing heterocycleoptionally substituted with one or more substituent selected from thegroup consisting of lower alkyl, hydroxy, keto, alkoxy, halogen, phenyl,amino, carboxyl or carboxyl ester, and fused phenyl.
 4. A compoundselected from the group consisting of

and all isomers, enantiomers, tautomers, racemates and polymorphsthereof.
 5. A pharmaceutical composition comprising a compound of claim1, 2, 3, and
 4. 6. A method of inhibiting a condition mediated by theα_(v)β₃ or α_(v)β₅ integrin comprising administering a therapeuticallyeffective amount of a compound of claim 1, 2, 3, or
 4. 7. The methodaccording to claim 6 wherein the condition treated is selected from thegroup consisting of tumor metastasis, solid tumor growth, angiogenesis,osteoporosis, humoral hypercalcemia of malignancy, smooth muscle cellmigration, restenosis, atheroscelososis, macular degeneration,retinopathy, and arthritis.